Compositions and methods for the treatment of presbyopia

ABSTRACT

The invention provides compositions and methods for the treatment of presbyopia. The compositions preferably use aceclidine separate or together with a cycloplegic agent and/or with a nonionic surfactant and viscosity enhancer, and or with low concentrations of a selective α-2 adrenergic receptor agonist.

BACKGROUND OF THE INVENTION

As a person ages the minimum distance from the eye at which an objectwill come into focus, provided distance vision is corrected or isexcellent unaided, increases. For example, a 10 year-old can focus on anobject or a “focal point” only three inches (0.072 meters) from theireye while still retaining excellent distance vision; a 40 year-old atsix inches (0.15 meters); and a 60 year-old at an inconvenient 39 inches(1.0 meter). This condition of increasing minimum focal length inindividuals with excellent unaided distance vision is called presbyopia,loosely translated as “old-man eye”.

Excellent unaided distance vision is also known as emmetropia. Theinability to focus on distant focal points is known as myopia and theinability to focus on near focal points is known as hyperopia.Specifically, “distance” vision is considered any focal point 1 meter ormore from the eye and near vision is any focal point less than 1 meterfrom the eye. The minimum focal length at which an object will come intofocus is known as the “near point”. The change in focus from distance tothe near point and any focal point in between is called accommodation.Accommodation is often measured in diopters. Diopters are calculated bytaking the reciprocal of the focal length (in meters). For example, thedecrease in accommodation from a 10 year-old eye to a 60 year-old eye isabout 13 diopters (1÷0.072 meters=13.89 diopters; 1÷1 meter=1 diopter).

The highest incidence of first complaint of presbyopia occurs in peopleages 42-44. Presbyopia occurs because as a person ages the eye'saccommodative ability which uses near reflex-pupil constriction,convergence of the eyes and particularly ciliary muscle contraction,decreases. This reduction in accommodation results in an inadequatechange in the normal thickening and increased curvature of the anteriorsurface of the lens that is necessary for the shift in focus fromdistant objects to near objects. Important near focus tasks affected bypresbyopia include viewing computer screens (21 inches) and readingprint (16 inches).

Presbyopia is a normal and inevitable effect of ageing and is the firstunmistakable sign for many in their forties that they are getting older.One study found that more than 1 billion people worldwide werepresbyopic in 2005. This same study predicted that number to almostdouble by the year 2050. If everyone over the age of 45 is considered tobe presbyopic, then an estimated 122 million people in the United Statesalone had presbyopia in 2010. As baby boomers reach the critical age,this number is only going to increase.

Presbyopia carries with it a stigma resulting from the limitation inability to quickly function at many tasks requiring focusing at bothdistant and near points, which once occurred almost immediately. In thepresbyopic patient, these tasks can be performed only by the use ofeyeglasses, contact lenses or after undergoing invasive surgery. Onesuch optical modification, the monovision procedure, can be executedwith the use of glasses, contact lenses or even surgery. The monovisionprocedure corrects one eye for near focus and the other eye for distancefocus. However, monovision correction is normally accompanied by loss ofdepth perception and distance vision particularly in dim light (e.g.night). Other surgical procedures that have been developed to relievepresbyopia include: (1) the implantation of intraocular lenses(INTRACOR®; registered trademark of Technolas Perfect Vision GMBH); (2)reshaping of the cornea (PresbyLASIK and conductive keratoplasty); (3)scleral band expansion; and (4) implantation of corneal inlays (FlexivueMicrolens®; registered trademark of PresbiBio LLC, Kamra®; registeredtrademark of AcuFocus, Inc. and Vue+). Kamra® corneal inlaysmanufactured by AcuFocus work by inlaying a pinhole on the cornea toincrease the depth of focus. A similar effect can be achieved withgeneral miotic agents, such as pilocarpine (a non-selective muscarinicacetylcholine receptor agonist), carbachol (a non-selective muscarinicacetylcholine receptor agonist), and phospholine iodide (anacetylcholinesterase inhibitor). These general miotic agents triggerincreased ciliary muscle contraction and induce accommodation of anyremaining reserves, improving near vision at the expense of distancevision in individuals who still retain some accommodative function.While these general miotic agents also create improved depth of focusvia a pinhole effect induced by pupillary miosis (i.e. constriction), tothe degree accommodation occurs, the pinhole effect only partiallyoffsets the induced accommodative myopia for distance. In some cases,such as with pilocarpine or carbachol, the induced accommodation maycreate up to 5 diopters or more of induced myopia resulting in inducedmyopia causing blurred distance vision generally and during shift of thefocal point from distance to near. These general miotic agents alsocause substantial redness, severe nasal congestion and create ciliarymuscle spasms, which commonly induces discomfort that can be severe andlong-lasting. In extreme cases, such ciliary muscle spasms can result inretinal detachment.

Miotic agents have been described in various patent and patentapplications for the treatment of presbyopia. U.S. Pat. Nos. 6,291,466and 6,410,544 describe the use of pilocarpine to regulate thecontraction of ciliary muscles to restore the eye to its resting stateand potentially restore its accommodative abilities.

US Patent Application Publication No. 2010/0016395 describes the use ofpilocarpine with the non-steroidal anti-inflammatory, diclofenac, toreduce brow ache from ciliary spasm and increase the time in which theciliary muscle contraction is regulated. International PCT ApplicationPublication WO/2013/041967 describes the use of pilocarpine withoxymetazoline or meloxicam to temporarily overcome ocular conditionssuch as presbyopia.

U.S. Pat. No. 8,299,079 (HEK Development LLC) describes the use ofdirect acting general miotic agents such as pilocarpine, carbachol andphospholine iodide with brimonidine at a concentration from 0.05% to3.0% w/v. However, the use of brimonidine concentrations at or above0.05% w/v results in increased rebound hyperemia. For example, reboundredness occurs in 25% of patients using brimonidine 0.20% w/v(Alphagan®, registered trademark of Allergan, Inc.) twice daily.

These attempts at miotic treatment for presbyopia all induce transientmyopia of several diopters reducing distance vision to about legalblindness or worse at the expense of improved near vision for the fullduration of their action, typically lasting several hours.

Thus, there is a need in the art for a treatment of presbyopia that isnon-invasive and convenient with minimal side effects. Specifically,there is a need for an ophthalmological composition that will allow aperson suffering from presbyopia to focus on near objects withoutsignificant side effects such as diminished distance vision, blurredvision, pain, redness, impaired night driving or incapacitating dimlight vision, induced nasal congestion, or risk of retinal detachment.Further, such treatment should provide quick onset in minutes and aduration of full effect of several hours during which a pupillary miosisof between about 1.65-2.40 mm and more preferably 1.80 mm-about 2.2 mmis achieved.

SUMMARY OF THE INVENTION

In certain embodiments, the present invention is directed tocompositions and methods for the treatment of presbyopia.

In certain embodiments, the present invention is directed tocompositions and methods for the treatment of presbyopia comprising amuscarinic agonist, wherein the muscarinic agonist preferentiallyactivates M1 and M3 muscarinic acetylcholine receptors. In still morepreferred embodiments the muscarinic agonist is more highly selectivefor M1 than M3. In most preferred embodiments the muscarinic agonistactivates M1 only.

In certain embodiments, the present invention is directed tocompositions and methods for the treatment of presbyopia comprising amuscarinic agonist of Formula I:

Formula II:

wherein:

-   -   R₁ is H, O, CH₃, an alkyl, acetyl, acyl, an aziridine, nitrile,        imine, nitryl-imine methyl substitution, nitryl-imine methyl        substitution with ester attached, an aromatic ring, a        substituted aromatic ring, an azide, acetamide, a pyridine, a        substituted pyridine, a pyrollidine, a substituted pyrollidine,        imidazole, a substituted imidazole, an imidazole wherein one or        more carbon atoms are replaced by O or S, a substituted        imidazole wherein one or more carbon atoms are replaced by O or        S, a benzimidazole, a substituted benzimidazole, a benzimidazole        wherein one or more carbon atoms are replaced by O or S, or a        substituted benzimidazole wherein one or more carbon atoms are        replaced by O or S;    -   R₂ is H, O, CH₃, an alkyl, acetyl, acyl, nitrile, imine,        nitryl-imine methyl substitution, or an ester-O-alkyl;    -   R₃ is H, CH₃; acyl, acetyl, or ester; and    -   R₄ is acyl, acetyl, ester, CH₃, an alkyl, an aromatic ring, a        substituted aromatic ring, cyclohexane, or a substituted        cyclohexane ring,    -   and wherein each of R₁ and R₂ independently substitute for a H        of a —CH₂— of the quinuclidine ring.

In certain embodiments, the present invention is directed tocompositions and methods for the treatment of presbyopia comprising amuscarinic agonist that preferentially activates M1 and M3 muscarinicacetylcholine receptors.

In certain embodiments, the present invention is directed tocompositions and methods for the treatment of presbyopia comprising amuscarinic agonist selected from the group consisting of aceclidine,talsaclidine, sabcomeline, cevimeline, WAY-132983, AFB267B (NGX267),AC-42, AC-260584, 77-LH-28-1, and LY593039 or any pharmaceuticallyacceptable salts, esters, analogues, prodrugs or derivatives thereof.

In certain embodiments, the present invention is directed tocompositions and methods for the treatment of presbyopia comprising amuscarinic agonist that activates only M1 muscarinic acetylcholinereceptors.

In certain other embodiments, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprisingaceclidine.

In certain other embodiments the present invention is directed to anophthalmological composition for the treatment of presbyopia comprisingaceclidine and a cycloplegic agent.

In certain other embodiments, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprisingaceclidine and a selective α-2 adrenergic receptor agonist.

In certain other embodiments, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprisingaceclidine, a cycloplegic agent and a selective α-2 adrenergic receptoragonist.

In certain other embodiments, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprisinga general miotic agent and a cycloplegic agent.

In certain other embodiments, the present invention is directed to anophthalmological composition of the present invention comprising:

-   -   a general miotic agent, a compound of Formula I or II, a        muscarinic agonist or aceclidine;    -   optionally a cycloplegic agent;    -   optionally a selective α-2 adrenergic receptor agonist;    -   a viscosity enhancer; and

a surfactant selected from the group consisting of an anionicsurfactant, a nonionic surfactant, and a combination thereof.

In certain other embodiments, the viscosity enhancer is carboxymethylcellulose; the anionic surfactant is selected from the group consistingof a gamma cyclodextrin, Captisol® (sulfobutylether(β-cyclodextrin,Captisol is a registered trademark of Cydex Pharmaceuticals), sodiumlauryl sulfate and sodium ester lauryl sulfate; and the nonionicsurfactant is selected from the group consisting of a poloxamer, apolysorbate, Span® 20-80 (sorbitan monolaurate, sorbitan monopalmitate,sorbitan monostearate, and sorbitan monooleate; Span is a registeredtrademark of Uniqema Americas Inc.), a polyoxyl alkyl, a cyclodextrinand derivatives thereof.

In certain other embodiments, the present invention is directed to anophthalmological composition of the present invention comprising:

-   -   a general miotic agent, a compound of Formula I or II, a        muscarinic agonist or aceclidine;    -   optionally a cycloplegic agent;    -   optionally a selective α-2 adrenergic receptor agonist; and        a surfactant selected from the group consisting of Captisol®        (sulfobutylether β-cyclodextrin), polyoxyl 40 stearate and        2-hydroxypropyl beta-cyclodextrin.

In certain other embodiments, the present invention is directed to anophthalmological composition of the present invention comprising:

-   -   a general miotic agent, a compound of Formula I or II, a        muscarinic agonist or aceclidine;    -   optionally a cycloplegic agent;    -   optionally a selective α-2 adrenergic receptor agonist;    -   a surfactant selected from the group consisting of Captisol®        (sulfobutylether β-cyclodextrin), polyoxyl 40 stearate and        2-hydroxypropyl beta-cyclodextrin; and    -   one or more additional non-ionic surfactants.

In certain other embodiments, the one or more additional non-ionicsurfactants is selected from the group consisting of poloxamer 188,polyoxyl 40 stearate, polyoxyl 35 castor oil, polysorbate, Span® 20-80(sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate,and sorbitan monooleate), tyloxapol and combinations thereof.

In certain other embodiments the present invention is directed to anophthalmological composition of the present invention comprising:

-   -   a general miotic agent, a compound of Formula I or II, a        muscarinic agonist or aceclidine;    -   optionally a cycloplegic agent; and    -   optionally a selective α-2 adrenergic receptor agonist,

wherein the selective α-2 adrenergic receptor agonist is selected fromthe group consisting of brimonidine, dexmedetomidine, fadolmidine andguanfacine.

In certain other embodiments, the present invention is directed to anophthalmological composition of the present invention comprising:

-   -   a general miotic agent, a compound of Formula I or II, a        muscarinic agonist or aceclidine;    -   optionally a cycloplegic agent; and    -   optionally a selective α-2 adrenergic receptor agonist,

wherein the cycloplegic agent is selected from the group consisting ofpirenzepine, tropicamide, Cyclogyl® (cyclopentolate hydrochloride;Cyclogyl is a registered trademark of Alcon Research, LTD),4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), xanomeline,otenzepad and a combination thereof; in preferred embodiments thecycloplegic agent is tropicamide.

In preferred embodiments, a composition of the present invention has apH greater than or equal to about 5.5, preferably greater than or equalto 6.0, more preferably greater than or equal to 6.5 and most preferablygreater than or equal to 7.0.

In certain other embodiments, the present invention is directed to anophthalmological composition of the present invention comprising:

-   -   a general miotic agent, a compound of Formula I or II, a        muscarinic agonist or aceclidine;    -   optionally a cycloplegic agent;    -   optionally a selective α-2 adrenergic receptor agonist; and    -   an in situ gel.

In preferred embodiments the in situ gel is selected from the groupconsisting of Carbopol® (polyacrylic acid; Carbopol is a registeredtrademark of Lubrizol Advanced Materials, Inc.) at a concentration fromabout 0.0001% to about 0.4% w/v, alginate, pectin, xanthan gum and guargum.

In preferred embodiments, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprising:

aceclidine at a concentration from about 0.25% to about 2.0% w/v;

tropicamide at a concentration from about 0.025% to about 0.1% w/v;

carboxymethyl cellulose at a concentration from about 0.1% to about 1.2%w/v; and

sodium chloride at a concentration from about 0.01% to about 1.0% w/v.

In preferred embodiments, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprising:

aceclidine at a concentration from about 0.25% to about 2.0% w/v;

tropicamide at a concentration from about 0.025% to about 0.1% w/v;

carboxymethyl cellulose at a concentration from about 0.1% to about 1.2%w/v;

sodium chloride at a concentration from about 0.01% to about 1.0% w/v;and

benzalkonium chloride at a concentration from about 0.007% to about0.01% w/v.

In preferred embodiments, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprising:

aceclidine at a concentration from about 0.25% to about 2.0% w/v;

tropicamide at a concentration from about 0.025% to about 0.1% w/v;

carboxymethyl cellulose at a concentration from about 0.1% to about 1.2%w/v;

sodium chloride at a concentration from about 0.01% to about 1.0% w/v;and

a surfactant at a concentration from about 1% to about 15% w/v.

In preferred embodiments, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprising:

-   -   aceclidine at a concentration from about 0.25% to about 2.0%        w/v;    -   tropicamide at a concentration from about 0.025% to about 0.1%        w/v;    -   carboxymethyl cellulose at a concentration from about 0.1% to        about 1.2% w/v;    -   sodium chloride at a concentration from about 0.01% to about        1.0% w/v; and    -   Captisol® (sulfobutylether β-cyclodextrin) at a concentration        from about 5.0% to about 6.0% w/v.

In preferred embodiments, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprising:

aceclidine at a concentration from about 0.25% to about 2.0% w/v;

tropicamide at a concentration from about 0.025% to about 0.1% w/v;

carboxymethyl cellulose at a concentration from about 0.1% to about 1.2%w/v;

sodium chloride at a concentration from about 0.01% to about 1.0% w/v;and

polyoxyl 40 stearate at a concentration from about 5.0% to about 6.0%w/v.

The present invention is further directed to a method for treatingpresbyopia comprising administering to a patient in need thereof acomposition of the present invention.

The present invention is further directed to a method for treatingpresbyopia comprising administering to a patient in need thereof acomposition comprising aceclidine and optionally, an α-2 adrenergicagonist and/or a cycloplegic agent,

wherein the treatment can be combined in a single formulation ormultiple formulations or by co-administration or a sequentialadministration of an α-2 adrenergic agonist and/or co-administration ora sequential administration of a cycloplegic agent, or preferablyco-administration or sequential administration of both.

The present invention is further directed to a method of increasing thevisual depth of field (i.e. depth of focus) comprising administering toa subject in need thereof a pharmaceutically effective amount of anophthalmological composition of the present invention.

The present invention is further directed to a method of increasing thevisual depth perception upon improving near vision unaided comprisingadministering to a subject in need thereof a pharmaceutically effectiveamount of an ophthalmological composition of the present invention inboth eyes (binocular vision), wherein such binocularity further enhancesnear vision beyond that of either eye separately.

The present invention is further directed to a method of inducing pupilmiosis comprising administering to a subject in need thereof apharmaceutically effective amount of an ophthalmological composition ofthe present invention.

The present invention is further directed to a method of inducing pupilmiosis comprising administering to a subject in need thereof apharmaceutically effective amount of an ophthalmological composition ofthe present invention, wherein the pupil miosis is from about 1.40 toabout 2.0 millimeters.

The present invention is further directed to a method of inducing pupilmiosis comprising administering to a subject in need thereof apharmaceutically effective amount of an ophthalmological composition ofthe present invention, wherein the pupil miosis is from about 1.50 toabout 1.70 millimeters.

The present invention is further directed to a method of inducing pupilmiosis comprising administering to a subject in need thereof apharmaceutically effective amount of an ophthalmological composition ofthe present invention, wherein the pupil miosis is from about 1.80 toabout 2.0 millimeters.

The present invention is further directed to a method of inducing pupilmiosis comprising administering to a subject in need thereof apharmaceutically effective amount of an ophthalmological composition ofthe present invention, wherein the pupil miosis is from about 1.50 toabout 1.70 millimeters and wherein the duration of the miotic effect isat least about 4 hours.

The present invention is further directed to a method of inducing pupilmiosis comprising administering to a subject in need thereof apharmaceutically effective amount of an ophthalmological composition ofthe present invention, wherein the pupil miosis is from about 1.50 toabout 1.70 millimeters and wherein the duration of the miotic effect isat least about 6 hours.

The present invention is further directed to a method of inducing pupilmiosis comprising administering to a subject in need thereof apharmaceutically effective amount of an ophthalmological composition ofthe present invention, wherein the pupil miosis is from about 1.50 toabout 1.70 millimeters and wherein the duration of the miotic effect isat least about 7.5 hours.

The present invention is further directed to a method of inducing pupilmiosis comprising administering to a subject in need thereof apharmaceutically effective amount of an ophthalmological composition ofthe present invention, wherein the pupil miosis is from about 1.50 toabout 1.70 millimeters and wherein the duration of the miotic effect isat least about 9 hours.

The present invention is further directed to a method of inducing pupilmiosis comprising administering to a subject in need thereof apharmaceutically effective amount of an ophthalmological composition ofthe present invention, wherein the pupil miosis is from about 1.50 toabout 2.50 millimeters and wherein the duration of the miotic effect isat least about 9 hours.

The present invention is further directed to a method of inducing pupilmiosis comprising administering to a subject in need thereof apharmaceutically effective amount of an ophthalmological composition ofthe present invention, wherein the pupil miosis is from about 1.80 toabout 2.00 millimeters and wherein the duration of the miotic effect isat least about 4 hours.

The present invention is further directed to a method of inducing pupilmiosis comprising administering to a subject in need thereof apharmaceutically effective amount of an ophthalmological composition ofthe present invention, wherein the pupil miosis is from about 1.80 toabout 2.00 millimeters and wherein the duration of the miotic effect isat least about 6 hours.

The present invention is further directed to a method of inducing pupilmiosis comprising administering to a subject in need thereof apharmaceutically effective amount of an ophthalmological composition ofthe present invention, wherein the pupil miosis is from about 1.80 toabout 2.00 millimeters and wherein the duration of the miotic effect isat least about 7.5 hours.

The present invention is further directed to a method of inducing pupilmiosis comprising administering to a subject in need thereof apharmaceutically effective amount of an ophthalmological composition ofthe present invention, wherein the pupil miosis is from about 1.80 toabout 2.00 millimeters and wherein the duration of the miotic effect isat least about 9 hours.

The present invention is further directed to a method of inducing pupilmiosis of about 1.35 to 2.0 mm without accommodation, or with minimalaccommodation of about 0.50 diopters or less, such that depth of focusenhancement is achieved without noticeable loss of distance vision orother degradation in distance vision quality.

The present invention is further directed to a method of inducing pupilmiosis of about 1.50 to 2.4 mm with clinically negligible accommodation,such that depth of focus enhancement is achieved without noticeable lossof distance vision or other degradation in distance vision quality, anda peak minimum pupil diameter typically about 30 to 60 minutes afterinstillation may be modulated by addition of a cycloplegic agent withoutinduction of irregular astigmatism, pupil mydriasis (i.e. dilation ofthe radial muscle of the iris), or substantial loss of duration ofeffect.

The present invention is further directed to a method of improvingvision in a subject with ammetropia (vision abnormality), comprisingadministering to a subject in need thereof a pharmaceutically effectiveamount of a composition of the present invention.The present invention is further directed to a method of improvingvision in a subject with ammetropia, comprising administering to asubject in need thereof a pharmaceutically effective amount of acomposition of the present invention, wherein ammetropia is selectedfrom the group consisting of nearsightedness, farsightedness, regularastigmatism, irregular astigmatism and high degrees of regularastigmatism.

The present invention is further directed at eliminating opticalaberrations induced by corneal irregularity, opacities, or very highdegrees of regular astigmatism that include regions adjacent orperipheral to the central 1.5 mm optical zone, and thereby inducingimproved visual acuity and quality of vision by filtering out theseaberrant optics in those suffering from irregular astigmatism or highdegrees of more regular astigmatism, such as occurs in conditions suchas keratoconus, photorefractive keratectomy induced corneal haze,diffuse lamellar keratitis (“DLK”) (post-lasik DLK), other iatrogeniccorneal induced irregularity such as cataract incision, glaucomafiltering blebs, implanted glaucoma valves, corneal inlays with orwithout removal, ectasia post corneal surgery (lasik), and secondary toinfection.

The present invention is further directed at improving acuity relativeto existing uncorrected refractive error. Upon this improved acuity,patients now requiring toric contact lenses for astigmatism with reducedcomfort and optics that may shift during each blink may in many casesrequire only non-toric soft contact lenses or no contact lenses.Further, those requiring gas permeable contact lenses may no longerrequire contact lenses or only require much more comfortable softcontact lenses. Patients with high degrees of astigmatism may nowrequire no correction or reduced astigmatic correction. Patients withsmall to moderate degrees of nearsightedness may require less correctionor no longer require correction. Patients with small to moderate degreesof hyperopia (farsightedness) may require no correction or reducedcorrection.

The present invention is directed to methods and ophthalmologicalcompositions for improving eye sight. In a preferred embodiment thepresent invention is directed to methods and ophthalmologicalcompositions for the treatment of presbyopia. In a more preferredembodiment the present invention is directed to ophthalmologicalcompositions comprising aceclidine. In a yet more preferred embodimentpresent invention is directed to ophthalmological compositionscomprising aceclidine and a low-dose cycloplegic agent. In a mostpreferred embodiment the present invention is directed toophthalmological compositions comprising aceclidine, a low-dosecycloplegic agent and a combination of inactive ingredients that makeeffective and/or enhance aceclidine.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graphical representation of the effects of pilocarpine andaceclidine with or without tropicamide and with or without a carrier onnear and distance vision in a patient over the age of 45.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compositions and methods oftreating presbyopia, irregular astigmatism, and/or refractive error,comprising administering to a patient in need thereof a pharmaceuticalcomposition comprising a muscarinic agonist that preferentiallyactivates M1 and M3 muscarinic acetylcholine receptors, preferablyactivate M1 more than M3 and most preferably aceclidine or itsderivatives. Aceclidine has been surprisingly and unexpectedlydiscovered to provide enhanced presbyopic reversal with negligible sideeffects day or night (when viewing includes one or more direct orreflected light sources) using compositions of the present invention.

The compositions and methods of the present invention treat presbyopiaby improving depth of focus in patients with presbyopia by administeringan ophthalmological composition to the eye that reduces pupil dilationin the dark or in dim light, produces a particular degree and durationof miosis without accommodation, provides cosmetic whitening and/orinduce redness prophylaxis. The compositions and methods of the presentinvention also do not cause significant pupil rebound, tachyphylaxis,ciliary spasms, induction of myopia or reduction in distance vision.Additionally, the compositions and methods of the present inventionallow for the further improvement in visual acuity and depth perceptionof binocular (both eyes) treatment. The ophthalmological composition ofthe present invention surprisingly creates a pupil of from about 1.5 toabout 2.4 mm at the anterior iris plane and about 2.0 mm at the cornealsurface with negligible increase in accommodative tone and with areduction or ablation of the redness that is otherwise a hallmark of theuse of miotic agents. This pupil miosis with greatly diminished orabsent accommodative tone is superior to the pinhole effect of theKamra® and Flexivue Microlens® corneal inlays. Pupil miosis is superiorbecause the constriction of the actual pupil does not result in theattendant severe night vision disturbance caused by the light scatteringborders of the pre-corneal pinholes created by the inlays. Further pupilmiosis provides a greater field of vision and transmission of morefocused light. The use of aceclidine has a minimal effect on thelongitudinal ciliary muscle, thus reducing risk of retinal detachmentwhen compared to the use of general muscarinic agonists such aspilocarpine and carbachol. The further inclusion of a cycloplegic agentresulted in only 0.04 mm of anterior chamber shallowing. Aceclidineparticularly as enhanced for the present invention also has greatermagnitude, duration, and control of minimum pupil diameter. Compositionsof the present invention achieve these advantages while havingnegligible effects on accommodation, thus avoiding the distance blurtypically seen in patients as a response to pilocarpine and/or carbacholinduced miosis. Any effects on accommodation may be further reduced ortotally eliminated in preferred embodiments with a cycloplegic agent.Aceclidine is capable of producing the increased depth of focus by pupilmiosis described in the present invention without the need of aselective α-2 adrenergic receptor agonist (“α-2 agonist”). Particularlyenhanced miosis occurs with use of compositions of the presentinvention, thus making it possible to use an α-2 agonist at lowconcentrations to reduce eye redness. Further, due to the apparent andsurprisingly selective nature of aceclidine, administration to the eyealmost exclusively affects pupil miosis rather than ciliary musclecontraction. Thus, the administration of aceclidine results in pupilmiosis without accommodation and attendant distance blur. However,aceclidine may cause some redness and brow ache, and without formulationenhancement of the present invention may produce less than optimal pupilmiosis or at extremely high concentration more than desired peak miosiswith added dimming of vision in dim or absent lighting.

Certain embodiments of the present invention enhance the discoveredpreferred degree of pupillary miosis by providing a consistent range ofeffect of about 1.50-2.20 mm for most patients using a preferredembodiment of a nonionic surfactant and viscosity enhancer. Similarbenefit may be achieved using other permeation enhancers, particularlyCarbopol® (polyacrylic acid), and various viscosity additives thatincrease drug residence time, such as xanthan gums, guar gum, alginate,and other in situ gels well known to experts in the art. The presentinvention further prevents nasal congestion otherwise occurring whensubstantial aceclidine levels reach the nasal mucosa, due to therheologic properties of the preferred embodiment.

The combination of aceclidine and a low concentration of a selective α-2adrenergic receptor agonist (α-2 agonist or α-2 adrenergic agonist),such as fadolmidine, brimonidine or guanfacine, allows for the desiredmiotic effect with diminished or no redness. The use of lowconcentrations of a selective α-2 agonist results in substantialreduction of hyperemia with greatly reduced risk of rebound hyperemiathat is found in concentrations of about 0.06% w/v or more. Furthermore,the use of low concentrations of selective α-2 agonist does notadversely modify the pupil constriction caused by aceclidine. Incontrast, the use of brimonidine 0.20% w/v, when topically applied forpupil modulation for night vision, result in tachyphylaxis of pupilmodulation due to α-2 receptor upregulation in almost 100% of treatedsubjects within four weeks of use.

Unexpectedly, the addition of a cycloplegic agent results in reductionof any brow ache or associated discomfort by further reducing the degreeof ciliary spasms on instillation without impairing the miotic response.This lack of impairment of the miotic response is an unexpectedsurprising discovery, as particular cycloplegic agents, such astropicamide, have known pupil dilating effects at concentrations as lowas 0.01% w/v (Grünberger J. et al., The pupillary response test as amethod to differentiate various types of dementia, Neuropsychiatr, 2009,23(1), pg 57). More specifically cycloplegic agents cause pupilmydriasis (i.e. dilation of the radial muscle of the iris). Further, theaddition of a cycloplegic agent to the miotic agent unexpectedlyincreases the time at which the pupil maintains the desired size rangewithout becoming too restricted. Peak miotic effect at 30-60 minutes canbe titrated in inverse relation to the cycloplegic concentration. Theconcentrations of tropicamide discovered in the present inventionapparently cause more relaxation of the ciliary muscle than the irisradial musculature. In fact, iris mydriasis is discovered to besuppressed by the addition of tropicamide to compositions containingconcentrations of aceclidine used in the present invention, with insteada more consistent level of miosis for the duration of the miotic effect.Additionally and quite surprisingly, unexpectedly, and beneficially theaddition of tropicamide can reduce the degree of peak pupil miosiswithout inducing mydriasis thereby creating a more constant and idealpupil size throughout the drug induced miosis. This more consistentpupil size allows for beneficial near and distance vision without theadverse dimming or loss of resolution due to diffraction limits at thevery reduced pupil sizes seen at peak pupil miosis (e.g. 1.25 mm).

General miotic agents, such as pilocarpine, carbachol and phospholinediesterase, are capable of causing pupil miosis resulting in improvednear vision of presbyopic patients. However, there is an inversereduction in distance vision associated with these general miotic agentsfrom miosis at peak effect and accommodation that is not seen withaceclidine. The co-administration of a cycloplegic agent with aceclidinesurprisingly results in an attenuation of this reduction in distancevision.

Comfort, safety, and efficacy of a preferred embodiment of anophthalmological composition of the present invention results from thepresence of a nonionic surfactant, such as cyclodextrin alpha, beta, orgamma chains, preferably 2-hydroxypropyl beta-cyclodextrin (“HPβCD”),and or sulfobutyl ether derivative of β-cyclodextrin (Captisol®),polyoxyl 40 stearate or poloxamer 407; a viscosity enhancing agent, suchas carboxymethyl cellulose (“CMC”); a tonicity adjustor, such as sodiumchloride; a preservative, such as benzalkonium chloride and a pH fromabout 5.0 to about 8.0. Further, an increase in the concentration of theviscosity agent and the electrolyte may result in reduced redness.Specifically, increasing CMC from 0.50% to 0.75% w/v (preferably 0.80%w/v) and sodium chloride from 0.25% to 0.50% w/v results in reducedredness.

DEFINITIONS

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, from acombination of the specified ingredients in the specified amounts.

As used herein, all numerical values relating to amounts, weights, andthe like, that are defined as “about” each particular value is plus orminus 10%. For example, the phrase “about 5% w/v” is to be understood as“4.5% to 5.5% w/v.” Therefore, amounts within 10% of the claimed valueare encompassed by the scope of the claims.

As used herein “% w/v” refers to the percent weight of the totalcomposition.

As used herein the term “subject” refers but is not limited to a personor other animal.

The term muscarinic receptor agonist (“muscarinic agonist”) encompassesagonists that activate muscarinic acetylcholine receptors (“muscarinicreceptors”). Muscarinic receptors are divided into five subtypes namedM1-M5. Muscarinic agonists of the present invention include thosemuscarinic agonists that preferentially activate M1 and M3 receptorsover M2, M4 and M5 receptors (“M1/M3 agonists”). M1/M3 agonists includebut are not limited to aceclidine, xanomeline, talsaclidine,sabcomeline, cevimeline, alvameline, arecoline, milameline, SDZ-210-086,YM-796, RS-86, CDD-0102A(5-[3-ethyl-1,2,4-oxasdiazol-5-yl]-1,4,5,6-tetrahydropyrimidinehydrocholoride), N-arylurea-substituted 3-morpholine arecolines,VUO255-035(N-[3-oxo-3-[4-(4-pyridinyl)-1-piperazinyl]propyl]-2,1,3-benzothiadiazole-4-sulfonamide),benzylquinolone carboxylic acid (BQCA), WAY-132983, AFB267B (NGX267),AC-42, AC-260584, chloropyrazines including but not limited to L-687,306, L-689-660, 77-LH-28-1, LY593039, and any quiniclidine ring with oneor more carbon substitutions particularly that include an ester, sulfur,or 5 or 6 carbon ring structure including with substituted nitrogen(s)and or oxygen(s), or any pharmaceutically acceptable salts, esters,analogues, prodrugs or derivatives thereof. A preferred M1/M3 agonist isaceclidine. In a preferred embodiment, muscarinic agonist of the presentinvention include those muscarinic agonist that preferentially activateM1 and M3 over M2, M4, and M5; and even more preferably activate M1 overM3. In a more preferred embodiment muscarinic agonist of the presentinvention include those muscarinic agonist that only activate M1.

The term “aceclidine” encompasses its salts, esters, analogues, prodrugsand derivatives including, but not limited to, aceclidine as a racemicmixture, aceclidine (+) enantiomer, aceclidine (−) enantiomer,aceclidine analogues, including, but not limited to, highly M1 selective1,2,5 thiadiazole substituted analogues like those disclosed in Ward. J.S. et al., 1,2,5-Thiadiazole analogues of aceclidine as potent mlmuscarinic agonists, J Med Chem, 1998, Jan. 29, 41(3), 379-392 andaceclidine prodrugs including but not limited to carbamate esters.

The term “selective α-2 adrenergic receptor agonists” or “α-2 agonist”encompasses all α-2 adrenergic receptor agonists which have a bindingaffinity of 900 fold or greater for α-2 over α-1 adrenergic receptors,or 300 fold or greater for α-2a or α-2b over α-1 adrenergic receptors.The term also encompasses pharmaceutically acceptable salts, esters,prodrugs, and other derivatives of selective α-2 adrenergic receptoragonists.

The term “low concentrations” or “low-dose” refers to concentrationsfrom between about 0.0001% to about 0.065% w/v; more preferably, fromabout 0.001% to about 0.035% w/v; even more preferably, from about 0.01%to about 0.035% w/v; and even more preferably, from about 0.03% to about0.035% w/v.

The term “brimonidine” encompasses, without limitation, brimonidinesalts and other derivatives, and specifically includes, but is notlimited to, brimonidine tartrate,5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline D-tartrate, and Alphagan®.

The terms “treating” and “treatment” refer to reversing, alleviating,inhibiting, or slowing the progress of the disease, disorder, orcondition to which such terms apply, or one or more symptoms of suchdisease, disorder, or condition.

The term “pharmaceutically acceptable” describes a material that is notbiologically or otherwise undesirable (i.e. without causing anunacceptable level of undesirable biological effects or interacting in adeleterious manner).

As used herein, the term “pharmaceutically effective amount” refers toan amount sufficient to effect a desired biological effect, such as abeneficial result, including, without limitation, prevention,diminution, amelioration or elimination of signs or symptoms of adisease or disorder. Thus, the total amount of each active component ofthe pharmaceutical composition or method is sufficient to show ameaningful subject benefit. Thus, a “pharmaceutically effective amount”will depend upon the context in which it is being administered. Apharmaceutically effective amount may be administered in one or moreprophylactic or therapeutic administrations.

The term “prodrugs” refers to compounds, including, but not limited to,monomers and dimers of the compounds of the invention, which havecleavable groups and become, under physiological conditions, compoundswhich are pharmaceutically active in vivo.

As used herein “salts” refers to those salts which retain the biologicaleffectiveness and properties of the parent compounds and which are notbiologically or otherwise harmful at the dosage administered. Salts ofthe compounds of the present inventions may be prepared from inorganicor organic acids or bases.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids or bases. The phrase “pharmaceutically acceptable salt” meansthose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. For example, S. M. Berge etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66: I et seq.

The salts can be prepared in situ during the final isolation andpurification of the compounds of the invention or separately by reactinga free base function with a suitable organic acid. Representative acidaddition salts include, but are not limited to acetate, adipate,alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate(isothionate),lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; arylalkyl halides likebenzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,hyaluronic acid, malic acid, sulphuric acid and phosphoric acid and suchorganic acids as oxalic acid, malic acid, maleic acid, methanosulfonicacid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium and aluminum salts and the likeand nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylammonium,dimethylammonium, trimethylammonium, triethylammonium, diethylammonium,and ethylammonium among others. Other representative organic aminesuseful for the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, piperazine and the like.

The term “ester” as used herein is represented by the formula —OC(O)A¹or —C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, a heteroaryl group or other suitablesubstituent.

Compositions of the Invention

In one embodiment, the present invention is directed to anophthalmological composition comprising aceclidine. In a preferredembodiment, aceclidine is at a concentration from about 0.25% to about2.0% w/v, more preferably from about 0.50% to about 1.90% w/v, stillmore preferably from about 1.25% to about 1.85% w/v, and most preferablyfrom about 1.35% to about 1.65% w/v. As aceclidine is a tertiary aminewith asymmetry, both a + and − optical isomer exist (where in somestudies (+) is more potent and in others it is felt (−) may be morepotent). For the above concentrations polarimetry demonstrated anexactly equal ratio of (+) and (−) isomer for these concentrations.Altering this ratio could therefore alter this concentration rangeproportional to a change in ratio.

The present invention is further directed to an ophthalmologicalcomposition comprising a muscarinic agonist, preferably a nonionicsurfactant above its critical micellar concentration for thecomposition, and a viscosity enhancing agent; or alternatively an insitu gelling agent. In preferred embodiments the initial viscosity ofthe composition on topical application is above 20 cps, preferably 50cps, and more preferably above 70 cps at low shear (1/s).

Nonionic surfactants suitable for the present invention includecyclodextrins, polyoxyl alkyls, poloxamers or combinations thereof, andmay include in addition combinations with other nonionic surfactantssuch as polysorbates. Preferred embodiments include polyoxyl 40 stearateand optionally Poloxamer 188, Poloxamer 407, Polysorbate 20, Polysorbate80, ionically charged (e.g. anionic) beta-cyclodextrins with or withouta butyrated salt (Captisol®) 2-hydroxypropyl beta cyclodextrin(“HPβCD”), alpha cyclodextrins, gamma cyclodextrins, Polyoxyl 35 castoroil, and Polyoxyl 40 hydrogenated castor oil or combinations thereof.Further, substitution of other nonionic surfactants compatible withophthalmological use allows for similar formulation advantages, whichmay included but is not limited to one or more of a nonionizingsurfactant such as poloxamer, poloxamer 103, poloxamer 123, andpoloxamer 124, poloxamer 407, poloxamer 188, and poloxamer 338, anypoloxamer analogue or derivative, polysorbate, polysorbate 20,polysorbate 40, polysorbate 60, polysorbate 80, any polysorbate analogueor derivative, cyclodextrin, hydroxypropyl-β-cyclodextrin,hydroxypropyl-γ-cyclodextrin, randomly methylated β-cyclodextrin,β-cyclodextrin sulfobutyl ether, γ-cyclodextrin sulfobutyl ether orglucosyl-β-cyclodextrin, any cyclodextrin analogue or derivative,polyoxyethylene, polyoxypropylene glycol, an polysorbate analogue orderivative, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene(200), polyoxypropylene glycol (70), polyoxyethylene hydrogenated castoroil, polyoxyethylene hydrogenated castor oil 60, polyoxyl, polyoxylstearate, nonoxynol, octyphenol ethoxylates, nonyl phenol ethoxylates,capryols, lauroglycol, PEG, Brij® 35(polyoxyethyleneglycol dodecylether; Brij is a registered trademark of Uniqema Americas LLC), glyceryllaurate, lauryl glucoside, decyl glucoside, or cetyl alcohol; orzwitterion surfactants such as palmitoyl carnitine, cocamide DEA,cocamide DEA derivatives cocamidopropyl betaine, or trimethyl glycinebetaine, N-2(2-acetamido)-2-aminoethane sulfonic acid (ACES),N-2-acetamido iminodiacetic acid (ADA),N,N-bis(2-hydroxyethyl)-2-aminoethane sulfonic acid (BES),2-[Bis-(2-hydroxyethyl)-amino]-2-hydroxymethyl-propane-1,3-diol(Bis-Tris), 3-cyclohexylamino-1-propane sulfonic acid (CAPS),2-cyclohexylamino-1-ethane sulfonic acid (CHES),N,N-bis(2-hydroxyethyl)-3-amino-2-hydroxypropane sulfonic acid (DIPSO),4-(2-hydroxyethyl)-1-piperazine propane sulfonic acid (EPPS),N-2-hydroxyethylpiperazine-N′-2-ethane sulfonic acid (HEPES),2-(N-morpholino)-ethane sulfonic acid (MES), 4-(N-morpholino)-butanesulfonic acid (MOBS), 2-(N-morpholino)-propane sulfonic acid (MOPS),3-morpholino-2-hydroxypropanesulfonic acid (MOPSO),1,4-piperazine-bis-(ethane sulfonic acid) (PIPES),piperazine-N,N′-bis(2-hydroxypropane sulfonic acid) (POPSO),N-tris(hydroxymethyl)methyl-2-aminopropane sulfonic acid (TAPS),N-[tris(hydroxymethyl)methyl]-3-amino-2-hydroxypropane sulfonic acid(TAPSO), N-tris(hydroxymethyl) methyl-2-aminoethane sulfonic acid (TES),2-Amino-2-hydroxymethyl-propane-1,3-diol (Tris), tyloxapol, and Span®20-80 (sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonostearate, and sorbitan monooleate). In certain embodiments theaddition of an anionic surfactant such as sodium lauryl sulfate and orsodium ester lauryl sulfate may be preferred.

Ophthalmological in situ gels which may be substituted for or added inaddition to one or more nonionic surfactants include but are not limitedto gelatin, carbomers of various molecular weights including carbomer934 P and 974 P, xanthan gums, alginic acid (alginate), guar gums,locust bean gum, chitosan, pectins and other gelling agents well knownto experts in the art.

In preferred embodiments the nonionic surfactant is polyoxyl 40 stearateat a concentration from about 1 to about 15% w/v, more preferably atabout 5.5% w/v.

In such preferred embodiment, polyoxyl 40 stearate is found to enhancethe redness reduction effect preferentially over aqueous solutions andother nonionic surfactants such as poloxamer 407, particularly in thepresence of an α-2 agonist.

Viscosity enhancers suitable for the present invention include, but arenot limited to, carboxymethyl cellulose (“CMC”), methylcellulose, methylcellulose 4000, hydroxymethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, hydroxyl propyl methyl cellulose 2906,carboxypropylmethyl cellulose, hydroxyethyl cellulose, or hydroxyethylcellulose, hyaluronic acid, dextran, polyethylene glycol, polyvinylalcohol, polyvinyl pyrrolidone, gellan, carrageenan, alignic acid,carboxyvinyl polymer or combinations thereof. In a preferred embodimentthe viscosity enhancer will have an equilibration viscosity between 10centipoise (“cps”) and 100 cps between eyelid blinks and 30 cps or less,preferably 20 cps or less and more preferably 15 cps or less during aneyelid blink. In a preferred embodiment the viscosity enhancer is 0.62%to 1.25% w/v CMC, more preferably from 0.75% to 0.87% w/v CMC (1%=2,500centipoise), and most preferably 0.80% w/v CMC (1% in water=2,500centipoise).

Not wishing to be held to particularly theory, it appears thecombination of nonionic surfactant and viscosity enhancer results innanometer diameter particles that are, for example, spheroid, othergeometric shaped rods or ellipsoids, that aggregate such as in bilayers.These particles are at low surface tension and may be at relatively highviscosity, both allowing prolonged residence time with minimal flow withtears exiting the lacrimal puncta thus allowing better penetration ofthe tear mucosal layer and cornea and reduced nasal mucosal penetrationand local effect as well as reduced systemic absorption. Once appliedtopically an initial viscosity well above 20 cps prevents nasolacrimaldrainage and nasal congestion from the aceclidine, which is a directvasodilating cholinergic drug and may otherwise cause some degree ofnasal congestion. This comfort is achieved without systemic side fromnasolacrimal vascular entry into the circulation, suppressing directeffects on nasal mucosa leading to nasal congestion as results fromaceclidine aqueous compositions.

The selective α-2 agonist may be included within the composition of thepresent invention or applied topically preferably just minutes before orless preferably just minutes afterward if additional means to reducenasal congestion or redness is desired for sensitive subjects. Selectiveα-2 agonists suitable for the present invention have minimal α-1 agonistactivity at low concentrations. For example, for brimonidine orfadolmidine, 1% to 2% w/v is considered extremely high, 0.5% to 1.0% w/vstill highly inductive of a-1 receptors and toxic for purposes of thepresent invention. Further, 0.10% to 0.5% w/v is still too high and even0.070% to 0.10% w/v is associated with a higher than preferred incidenceof rebound hyperemia (however, for dexmedetomidine, its greaterlipophilicity and intraocular penetration reduces rebound risk in thisrange). Only 0.065% w/v or below is potentially acceptable, where formost α-2 agonists, depending on degree of selectivity 0.050% w/v or evenmore preferably 0.035% w/v or less is desired. On the other hand somedegree of useful activity may occur at one or more orders of magnitudefurther reduction of concentration. The preferred embodiments,brimonidine, fadolmidine and guanfacine, of the present inventionpreferentially stimulate α-2 adrenergic receptors, and even morepreferably α-2b adrenergic receptors so that α-1 adrenergic receptorsare not stimulated sufficiently enough to cause excessive large vesselarteriolar constriction and vasoconstrictive ischemia. In addition, ithas been discovered that preventing or reducing redness for drugs thatotherwise directly induce redness, such as the acetylcholine agonist,aceclidine, enhances compliance for sensitive subjects that may haveinduced redness or nasal congestion even with formulations of thepresent invention that do not include an α-2 agonist. However, becauseα-2 agonists are shifted to their ionized equilibrium an acidic pH issomewhat offset by the fact such agonists exert greater affect atneutral or alkaline pH. Therefore each α-2 agonist has a preferred pHrange depending on its lipophilicity and pKa value when added to theinventive compositions with aceclidine. For the present invention whilepH range of 5.0 to 8.0 is tolerated, preferred embodiments are at pH 5.5to 7.5 and more preferably 6.5 to 7.0. Further, it has been discoveredthat cyclodextrins and/or polyoxyl 40 stearate as a nonionic surfactantcomponent or as the sole nonionic surfactant, result in a greaterwhitening effect when the α-2 agonist is included in the compositionrather than poloxamer 407. The α-2 agonist may optionally be appliedseparately or in certain preferred embodiments with formulations of thepresent invention that do not include an α-2 agonist, such as thoseformulas with polyoxyl 40 stearate 5.5% w/v as the non-ionic surfactant,although the α-2 agonist is not required except for occasional sensitivesubjects. Fadolmidine represents the α-2 agonist with highesthydrophilicity and therefore high surface retention for the presentinvention. Guanfacine is also highly selective and hydrophilic.Brimonidine is highly selective with moderate lipophilicity. Finally,dexmedetomidine has high selectivity with high lipophilicity that may beused with less efficacy for reducing redness for the purposes of thepresent invention (although possibly inducing fatigue as a side effectin some patients). In a preferred embodiment using polyoxyl 40 stearate5.5% w/v; CMC 0.80% w/v; NaCl 0.037% w/v; EDTA 0.015% w/v, borate buffer5 mM and BAK 0.007% w/v results in redness of about 1.0 to 1.5 out of 4which is transient lasting about ten minutes, and by 30 minutes returnsto about baseline.

In one embodiment, the selective α-2 adrenergic receptor agonist is acompound which has binding affinity of about 900 fold or greater, evenmore preferably about 1000 fold or greater, and most preferably, about1500 fold or greater.

The selective α-2 adrenergic receptor agonist may be present at aconcentration from between about 0.0001% to about 0.065% w/v; morepreferably, from about 0.001% to about 0.035% w/v; even more preferably,from about 0.01% to about 0.035% w/v; and even more preferably, fromabout 0.020% to about 0.035% w/v.

In one embodiment, the selective α-2 adrenergic receptor is selectedfrom the group consisting of brimonidine, guanfacine, fadolmidine,dexmedetomidine,(+)-(S)-4-[1-(2,3-dimethyl-phenyl)-ethyl]-1,3-dihydro-imidazole-2-thione,1-[(imidazolidin-2-yl)imino]indazole, and mixtures of these compounds.Analogues of these compounds that function as highly selective α-2agonists may also be used in compositions and methods of the presentinvention.

In a more preferred embodiment, the selective α-2 agonist is selectedfrom the group consisting of fadolmidine, guanfacine and brimonidine. Ina yet more preferred embodiment the selective α-2 agonist is brimonidinein the form of a salt at a concentration of 0.025% to 0.065% w/v, morepreferably from 0.03% to 0.035% w/v. In a preferred embodiment, the saltis a tartrate salt.

In another yet more preferred embodiment, the selective α-2 agonist isfadolmidine at a concentration from about 0.005% to about 0.05% w/v,more preferably from 0.02% to about 0.035% w/v in the form of ahydrochloride (“HCl”) salt.

In another yet more preferred embodiment, the selective α-2 agonist isguanfacine at a concentration from about 0.005% to about 0.05% w/v, morepreferably from 0.02% to about 0.035% w/v in the form of an HCl salt.

In another yet more preferred embodiment, the selective α-2 agonist isdexmedetomidine at a concentration from about 0.005% to about 0.05% w/v,more preferably from 0.04% to about 0.05% w/v in the form of an HClsalt.

In another preferred embodiment a pH less than physiologic pH is foundto enhance the whitening effect for brimonidine, preferably pH 4.5 to6.5, and more preferably pH 5.5 to 6.0. However, redness reduction isachieved at all pHs, and enhancement of aceclidine absorption occurs atalkaline pH, such that more effect occurs from a given concentration,and therefore while effective at pH ranges from 4.5 to 8.0, pH range of6.5 to 7.5 is preferred for the present invention, and 7.0 to 7.5 mostpreferred.

The present invention is further directed to an ophthalmologicalcomposition further comprising a cycloplegic agent. It is a surprisingand totally unexpected discovery of the present invention that certaincycloplegic agents can be combined with miotic agents, particularly forthe present invention, aceclidine, without reducing miotic onset,magnitude, or duration; and further blunt the normally attendant spikein miotic effect coinciding with time of peak absorption in aqueousformulations to provide a constant miosis versus time after onset from15 to 30 minutes to 6 to 10 hours depending on the desired formulation.The addition of the cycloplegic agent also reduces any residualassociated discomfort that may otherwise occur soon after instillation,which presumably is a result of ciliary spasms or excessive pupillarymiosis.

Cycloplegic agents suitable for the present invention include, but arenot limited to, atropine, Cyclogyl® (cyclopentolate hydrochloride),hyoscine, pirenzepine, tropicamide, atropine,4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP), AF-DX 384,methoctramine, tripitramine, darifenacin, solifenacin (Vesicare),tolterodine, oxybutynin, ipratropium, oxitropium, tiotropium (Spriva),and otenzepad (a.k.a. AF-DX 116 or11-{[2-(diethylamino)methyl]-1-piperidinyl }acetyl]-5,11dihydro-6H-pyrido [2,3b] [1,4]benzodiazepine-6-one). In apreferred embodiment the cycloplegic agent is tropicamide at aconcentration from about 0.01% to about 0.10% w/v, more preferably fromabout 0.025% to about 0.080% w/v and still more preferably from about0.04% to about 0.06% w/v. In another preferred embodiment thecycloplegic agent is a mixture of tropicamide at a concentration fromabout 0.04% to about 0.07% w/v or pirenzepine or otenzepad at aconcentration from about 0.002% to about 0.05% w/v.

In a preferred embodiment, tropicamide 0.01% w/v was found to slightlyreduce brow ache, 0.030% w/v to further reduce brow ache and from 0.04%to about 0.07% w/v to completely eliminate brow ache without reductionof the average pupillary miosis diameter over duration of effect.Tropicamide in preferred embodiments has demonstrated completelyunexpected sensitivity of effect, where at about 0.04% w/v unexpectedlyand very effectively reduces or eliminates brow ache and ciliary spasmpain, becoming very noticeably further reduced at 0.042% w/v and absentat 0.044% w/v in a preferred embodiment with no cycloplegia (surprisingdue to its common use as a pupil dilating agent). Yet, tropicamide didnot reduce the mean degree of pupil miosis, the time of onset of pupilmiosis or the subsequent visual benefits. On the contrary, tropicamideblunted the peak miosis seen in aqueous formulations to create a smoothconsistent miotic effect over time. It allowed modulation of peak pupilmiosis to achieve a more even effect over time with no dilation as hasbeen found with its prior use. Specifically, tropicamide is useful toprevent transient constriction below 1.50 mm at 30 to 60 minutesfollowing aceclidine in some embodiments and to reduce transientexcessive and undesirable dimming of vision that may otherwise occur atpeak onset of about 30 minutes. As an example, an ophthalmologicalcomposition comprising 1.53% w/v aceclidine, 5% w/v HPβCD, 0.75% w/vCMC, 0.25% w/v NaCl, 0.01% w/v BAK and a phosphate buffer at pH 7.0; or1.45% w/v aceclidine; 5.5% w/v polyoxyl 40 stearate; 0.80% w/v CMC;0.037% w/v NaCl; 0.015% w/v EDTA; 0.007% w/v BAK and 5 mM phosphatebuffer at a pH 7.0; was varied from 0.040% w/v tropicamide, wheremoderate dimming was noted, to 0.044% w/v tropicamide where dimmingbecame almost undetectable other than in extremely dim light conditions.This additional pupil size modulation with a cycloplegic agent allowsaceclidine concentrations sufficient for prolonged effect while bluntingthe attendant peak excessive constriction that is undesirable as well asany uncomfortable brow ache. Surprisingly and due to its short-actingnature, tropicamide achieves this blunting effect without causingmydriasis. Further, in a preferred embodiment, tropicamide 0.014% w/vwas found to reduce brow ache, 0.021% w/v to further reduce brow acheand from 0.028% to 0.060% w/v and in some embodiments up to 0.09% w/v tocompletely eliminate brow ache without cycloplegia (i.e. paralysis ofciliary muscle of the eye).

It has been found for a racemic 50:50 mixture of (+) and (−) aceclidineoptical isomers (where in some studies (+) is more potent and in othersit is felt (−) may be more potent) tropicamide effects may varydepending on the ratio of aceclidine to tropicamide. For example, in anophthalmological composition of the present invention comprising 1.55%w/v aceclidine, 5.5% w/v HPβCD or in a preferred embodiment polyoxyl 40stearate, 0.75% w/v CMC (1%=2,500 centipoise), 0.25% w/v NaCl, and 0.01%w/v BAK and at pH 7.5, 0.042% w/v tropicamide can be differentiated fromeven 0.035% w/v, with the former demonstrating normal indoor nightvision and the latter slight dimming that becomes more noticeable atstill lower concentrations. At higher concentrations, such as from about0.075% to about 0.090% w/v tropicamide, loss of optimal range pupilconstriction 1.50 mm to 1.80 mm range begins, and frank mydriasis athigher concentrations begins to occur. As isomer ratio may alter theeffective concentration, this must be factored into the clinicalefficacy anticipated using aceclidine; for preferred embodiments of thepresent invention a polarimeter was used to determine an exact 50:50isomer ratio was used (personal communication Toronto ResearchChemicals).

FIG. 1 shows the effect of a miotic agent with or without a cycloplegicagent and with or without a carrier. Subject is an emmetrope over theage of 45 with a baseline near vision of 20.100 and baseline distancevision of 20.20. Topical administration to the eye of 1% w/v pilocarpinein saline solution results in an improvement of near vision to 20.40 (8a), however this improvement comes at the expense of a reduction indistance vision to 20.100 (8 b). The addition of 0.015% w/v tropicamideresults in an improvement of near vision to 20.25 (9 a) and a lesseningof the reduction of distance vision to 20.55 (9 b), though in certaininstances with some induced irregular astigmatism (mildly blotched areasin reading field of vision). Topical administration of 1.55% w/vaceclidine in saline solution results in an improvement of near visionto 20.40 for an extended time period of 6 hrs (10 a) without any effecton the baseline distance vision (10 b). 10 c and 10 d show the effectsof administering aceclidine in a carrier composed of 5.5% w/v2-hydroxypropyl beta cyclodextrin, 0.75% w/v CMC (1%=2,500 centipoise),0.25% w/v NaCl, and 0.01% w/v BAK. As seen in 10 c the carrier increasesthe beneficial effect of aceclidine resulting in better than 20.20 nearvision. As seen in 10 d a similar increase in distance vision occurs. 10e and 10 f show the effects of adding 0.042% w/v tropicamide to theaceclidine in the carrier. As seen in 10e near vision is improved to20.15 with a quicker onset of maximum visual acuity. As seen in 10 f asimilar improvement is seen in distance vision. Taken together, FIG. 1shows that aceclidine is capable of temporarily correcting near visionin a presbyopic subject without affecting the baseline distance vision.Similar results can be achieved with a different miotic agent,pilocarpine, with the addition of a cycloplegic agent such astropicamide. A proper drug carrier can also have a beneficial effect.

The present invention is further directed to an ophthalmologicalcomposition further comprising a tonicity adjustor and a preservative.

A tonicity adjustor can be, without limitation, a salt such as sodiumchloride (“NaCl”), potassium chloride, mannitol or glycerin, or anotherpharmaceutically or ophthalmologicalally acceptable tonicity adjustor.In certain embodiments the tonicity adjustor is 0.037% w/v NaCl,

Preservatives that can be used with the present invention include, butare not limited to, benzalkonium chloride (“BAK”), chlorobutanol,thimerosal, phenylmercuric acetate, disodium ethylenediaminetetraaceticacid, phenylmercuric nitrate, perborate or benzyl alcohol. In apreferred embodiment the preservative is BAK at a concentration of about0.001% to about 1.0% w/v, more preferably at a concentration of about0.007% w/v. In another preferred embodiment the preservative isperborate at a concentration of 0.01% to about 1.0% w/v, more preferablyat a concentration of about 0.02% w/v.

Various buffers and means for adjusting pH can be used to prepareophthalmological compositions of the invention. Such buffers include,but are not limited to, acetate buffers, citrate buffers, phosphatebuffers and borate buffers. It is understood that acids or bases can beused to adjust the pH of the composition as needed, preferably of 1 to10 mM concentration, and more preferably about 5 mM. In a preferredembodiment the pH is from about 4.0 to about 8.0, in a more preferredembodiment the pH is from about 5.0 to about 7.0.

The present invention is further directed to an ophthalmologicalcomposition further comprising an antioxidant. Antioxidants that can beused with the present invention include but are not limited to disodiumethylenediaminetetraacetic acid at a concentration from about 0.005% toabout 0.50% w/v, citrate at a concentration from about 0.01% to about0.3% w/w, dicalcium diethylenetriamine pentaacetic acid (“Ca2DTPA”) at aconcentration from about 0.001% to about 0.2% w/v, preferably about0.01% w/v Ca2DTPA which can be formulated by adding 0.0084% w/v Ca(OH)₂and 0.0032% w/v pentetic acid to the formulation and mixing slowly.Further combinations of antioxidants can be used. Other antioxidantsthat can be used with the present invention include those well known toexperts in the art such as ethylenediaminetetraacetic acid at aconcentration from about 0.0001% to about 0.015% w/v.

It is a surprising and unexpected discovery that topical formulations ofthe present invention, particularly one of the preferred embodimentscomprising aceclidine 1.35% to 1.55% w/v; 5.5% w/v polyoxyl 40 stearate;0.80% w/v CMC; 0.037% w/v NaCl; 0.015% w/v EDTA; 0.007% w/v BAK; and 5mMphosphate buffer at pH 7.0 result in considerably prolonged contact lenswear and comfort after a single instillation daily. The single daily useof the preferred embodiments allowed a subject with dry eye to sleep inhis lenses for one week periods where previously even after a singlenight vision would be blurred and contact lenses coated with filmrequiring removal and cleaning or replacement (see Example 7).

The following representative embodiments are provided solely forillustrative purposes and are not meant to limit the invention in anyway.

Representative Embodiments

In certain embodiments, the present invention is directed tocompositions and methods for the treatment of presbyopia comprising amuscarinic agonist of Formula I:

Formula II:

wherein:

-   -   R₁ is H, O, CH₃, an alkyl, acetyl, acyl, an aziridine, nitrile,        imine, nitryl-imine methyl substitution, nitryl-imine methyl        substitution with ester attached, an aromatic ring, a        substituted aromatic ring, an azide, acetamide, a pyridine, a        substituted pyridine, a pyrollidine, a substituted pyrollidine,        imidazole, a substituted imidazole, an imidazole wherein one or        more carbon atoms are replaced by O or S, a substituted        imidazole wherein one or more carbon atoms are replaced by O or        S, a benzimidazole, a substituted benzimidazole, a benzimidazole        wherein one or more carbon atoms are replaced by O or S, or a        substituted benzimidazole wherein one or more carbon atoms are        replaced by O or S;    -   R₂ is H, O, CH₃, an alkyl, acetyl, acyl, nitrile, imine,        nitryl-imine methyl substitution, or an ester-O-alkyl;    -   R₃ is H, CH₃; acyl, acetyl, or ester; and    -   R₄ is acyl, acetyl, ester, CH₃, an alkyl, an aromatic ring, a        substituted aromatic ring, cyclohexane, or a substituted        cyclohexane ring,    -   and wherein each of R₁ and R₂ independently substitute for a H        of a —CH₂— of the quinuclidine ring.

In certain embodiments, the present invention is directed tocompositions and methods for the treatment of presbyopia comprising amuscarinic agonist that preferentially activates M1 and M3 muscarinicacetylcholine receptors.

In certain embodiments, the present invention is directed tocompositions and methods for the treatment of presbyopia comprising amuscarinic agonist that activates only M1 muscarinic acetylcholinereceptors.

In certain other embodiments, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprisingaceclidine.

In certain other embodiments, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprisingaceclidine and a cycloplegic agent.

In certain other embodiments, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprisingaceclidine, a cycloplegic agent and a selective α-2 adrenergic receptoragonist.

In certain other embodiments, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprisinga general miotic agent and a cycloplegic agent.

In certain other embodiments, the present invention is directed to anophthalmological composition of the present invention comprising:

a general miotic agent, a compound of Formula I or II, a muscarinicagonist or aceclidine;

optionally a cycloplegic agent;

optionally a selective α-2 adrenergic receptor agonist;

a viscosity enhancer; and

a surfactant selected from the group consisting of an anionicsurfactant, a nonionic surfactant, and a combination thereof.

In certain other embodiments, the viscosity enhancer is carboxymethylcellulose and the anionic surfactant is selected from the groupconsisting of a gamma cyclodextrin, Captisol® (sulfobutyletherβ-cyclodextrin), sodium lauryl sulfate and sodium ester lauryl sulfateand the nonionic surfactant is selected from the group consisting of apoloxamer, a polysorbate, Span® 20-80(sorbitan monolaurate, sorbitanmonopalmitate, sorbitan monostearate, and sorbitan monooleate), apolyoxyl alkyl, a cyclodextrin and derivatives thereof.

In certain other embodiments, the present invention is directed to anophthalmological composition of the present invention comprising:

-   -   a general miotic agent, a compound of Formula I or II, a        muscarinic agonist or aceclidine;    -   optionally a cycloplegic agent;    -   optionally a selective α-2 adrenergic receptor agonist; and        a surfactant selected from the group consisting of Captisol®        (sulfobutylether β-cyclodextrin), polyoxyl 40 stearate and        2-hydroxypropyl beta-cyclodextrin.

In certain other embodiments, the present invention is directed to anophthalmological composition of the present invention comprising:

-   -   a general miotic agent, a compound of Formula I or II, a        muscarinic agonist or aceclidine;    -   optionally a cycloplegic agent;    -   optionally a selective α-2 adrenergic receptor agonist;    -   a surfactant selected from the group consisting of Captisol®        (sulfobutylether β-cyclodextrin), polyoxyl 40 stearate and        2-hydroxypropyl beta-cyclodextrin; and one or more additional        non-ionic surfactants selected from the group consisting of        poloxamer 188, polyoxyl 40 stearate, polyoxyl 35 castor oil,        polysorbate, a Span® 20-80 (sorbitan monolaurate, sorbitan        monopalmitate, sorbitan monostearate, and sorbitan monooleate),        tyloxapol and combinations thereof.

In certain other embodiments, the present invention is directed to anophthalmological composition of the present invention comprising:

-   -   a general miotic agent, a compound of formula I or II, a        muscarinic agonist or aceclidine;    -   optionally a cycloplegic agent; and    -   optionally a selective α-2 adrenergic receptor agonist,    -   wherein the selective α-2 adrenergic receptor agonist is        selected from the group consisting of brimonidine,        dexmedetomidine, fadolmidine and guanfacine.

In certain other embodiments, the present invention is directed to anophthalmological composition of the present invention comprising:

-   -   a general miotic agent, a compound of Formula I or II, a        muscarinic agonist or aceclidine;    -   optionally a cycloplegic agent; and    -   optionally a selective α-2 adrenergic receptor agonist,

wherein the cycloplegic agent is selected from the group consisting ofpirenzepine, tropicamide, Cyclogyl® (cyclopentolate hydrochloride),4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), xanomeline,otenzepad and a combination thereof.

In preferred embodiments, a composition of the present invention has apH greater than or equal to about 5.5

In certain other embodiments the present invention is directed to anophthalmological composition of the present invention comprising:

-   -   a general miotic agent, a compound of Formula I or II, a        muscarinic agonist or aceclidine;    -   optionally a cycloplegic agent;    -   optionally a selective α-2 adrenergic receptor agonist; and    -   an in situ gel selected from the group consisting of Carbopol®        (polyacrylic acid) at a concentration from about 0.0001% to        about 0.4% w/v, alginate, pectin, xanthan gum and guar gum.

In a preferred embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.53% w/v;

tropicamide at a concentration of about 0.044% w/v;

carboxymethyl cellulose at a concentration of about 0.80% w/v;

sodium chloride at a concentration of about 0.75% w/v;

benzalkonium chloride at a concentration of about 0.01% w/v;

and phosphate buffer at a concentration of about 5 millimolar,

wherein the pH is about 8.0.

In another preferred embodiment, the ophthalmological compositioncomprises:

aceclidine at a concentration of about 1.53% w/v;

tropicamide at a concentration of about 0.044% w/v;

brimonidine at a concentration of about 0.042% w/v;

carboxymethyl cellulose at a concentration of about 0.80% w/v;

sodium chloride at a concentration of about 0.75% w/v;

benzalkonium chloride at a concentration of about 0.01% w/v;

and phosphate buffer at a concentration of about 5 millimolar,

wherein the pH is about 8.0.

In a most preferred embodiment, the ophthalmological compositioncomprises:

aceclidine at a concentration of about 1.45% w/v;

tropicamide at a concentration of about 0.044% w/v;

polyoxyl 40 stearate at a concentration of about 5.5% w/v;

carboxymethyl cellulose at a concentration of about 0.8% w/v;

sodium chloride at a concentration of about 0.37% w/v;

disodium ethylenediaminetetraacetic acid at a concentration of about0.015% w/v;

benzalkonium chloride at a concentration of about 0.007% w/v; and

phosphate buffer at a concentration of about 5 millimolar;

and a pH of about 7.0;

where brimonidine 0.40% w/v may be optionally added for slight lesseningof transient redness for about the first 10-20 minutes afterinstillation.

In another embodiment, the ophthalmological composition comprises:

-   -   aceclidine at a concentration of about 1.35% w/v;    -   tropicamide at a concentration of about 0.044% w/v;    -   Captisol® (sulfobutylether β-cyclodextrin) at a concentration        from about 5.0% to about 6.0% w/v;    -   carboxymethyl cellulose at a concentration from about 0.90% to        about 1.2% w/v;    -   sodium chloride at a concentration from about 0.025% to about        0.50% w/v; and    -   a buffer at a concentration from about 4.0 millimolar to about        5.0 millimolar selected from the group consisting of phosphate        buffer and borate buffer.        In another embodiment, the ophthalmological composition        comprises:    -   aceclidine at a concentration of about 1.35% w/v;    -   tropicamide at a concentration of about 0.044% w/v;    -   Captisol® (sulfobutylether β-cyclodextrin) at a concentration        from about 5.0% to about 6.0% w/v;    -   carboxymethyl cellulose at a concentration from about 0.90% to        about 1.2% w/v;    -   sodium chloride at a concentration from about 0.025% to about        0.50% w/v, preferably from about 0.037% to about 0.05% w/v;    -   optionally, benzalkonium chloride at a concentration of about        0.007% w/v or greater; and    -   a buffer at a concentration from about 4.0 millimolar to about        5.0 millimolar selected from the group consisting of phosphate        buffer and borate buffer.        In another embodiment, the ophthalmological composition        comprises:    -   aceclidine at a concentration of about 1.35% w/v;    -   tropicamide at a concentration of about 0.044% w/v;    -   Captisol® (sulfobutylether β-cyclodextrin) at a concentration        from about 5.0% to about 6.0% w/v;    -   carboxymethyl cellulose at a concentration from about 0.90% to        about 1.2% w/v;    -   sodium chloride at a concentration from about 0.025% to about        0.50% w/v;    -   mannitol at a concentration of about 4.0% w/v; and    -   a buffer at a concentration from about 4.0 millimolar to about        5.0 millimolar selected from the group consisting of phosphate        buffer and borate buffer.        In another embodiment, the ophthalmological composition        comprises:    -   aceclidine at a concentration of about 1.35% w/v;    -   tropicamide at a concentration of about 0.044% w/v;    -   Captisol® (sulfobutylether β-cyclodextrin) at a concentration        from about 5.0% to about 6.0% w/v;    -   carboxymethyl cellulose at a concentration from about 0.90% to        about 1.2% w/v;    -   sodium chloride at a concentration from about 0.025% to about        0.50% w/v;    -   an antioxidant selected from the group consisting of disodium        ethylenediaminetetraacetic acid at a concentration from about        0.005% to about 0.50% w/v, citrate at a concentration from about        0.01% to about 0.3% w/v, Ca2DTPA at a concentration from about        0.001% to about 0.2% w/v and a combination thereof, preferably        ethylenediaminetetraacetic acid at a concentration from about        0.0001% to about 0.015% w/v; and    -   a buffer at a concentration from about 4.0 millimolar to about        5.0 millimolar selected from the group consisting of phosphate        buffer and borate buffer.        In another embodiment, the ophthalmological composition        comprises:    -   aceclidine at a concentration of about 1.35% w/v;    -   tropicamide at a concentration of about 0.044% w/v;    -   Captisol® (sulfobutylether β-cyclodextrin) at a concentration        from about 5.0% to about 6.0% w/v;    -   carboxymethyl cellulose at a concentration from about 0.90% to        about 1.2% w/v;    -   sodium chloride at a concentration from about 0.025% to about        0.50% w/v;    -   an α-2 adrenergic receptor agonist at a concentration from about        0.025% to about 0.045% w/v selected form the group consisting of        brimonidine, fadolmidine and guanfacine; and    -   a buffer at a concentration from about 4.0 millimolar to about        5.0 millimolar selected from the group consisting of phosphate        buffer and borate buffer.        In another embodiment, the ophthalmological composition        comprises:    -   aceclidine at a concentration of about 1.35% w/v;    -   tropicamide at a concentration of about 0.044% w/v;    -   polyoxyl 40 stearate at a concentration from about 5.0% to about        6.0% w/v;    -   carboxymethyl cellulose at a concentration of about 0.80% w/v;    -   sodium chloride at a concentration from about 0.025% to about        0.05% w/v, preferably from about 0.037% to about 0.05% w/v; and    -   a buffer at a concentration from about 4.0 millimolar to about        5.0 millimolar selected from the group consisting of phosphate        buffer and borate buffer.        In another embodiment, the ophthalmological composition        comprises:    -   aceclidine at a concentration of about 1.35% w/v;    -   tropicamide at a concentration of about 0.044% w/v;    -   polyoxyl 40 stearate at a concentration from about 1% to 10%,        and more preferably, from about 5.0% to about 6.0% w/v;    -   carboxymethyl cellulose at a concentration of about 0.80% to        0.90% w/v;    -   sodium chloride at a concentration from about 0.025% to about        0.90%, and more preferably 0.05% w/v;    -   optionally, cocamidopropyl betaine at a concentration of about        0.1% w/v; and    -   a buffer at a concentration from about 4.0 millimolar to about        5.0 millimolar selected from the group consisting of phosphate        buffer and borate buffer.        In another embodiment, the ophthalmological composition        comprises:    -   aceclidine at a concentration of about 1.35% w/v;    -   tropicamide at a concentration of about 0.044% w/v;    -   polyoxyl 40 stearate at a concentration from about 5.0% to about        6.0% w/v;    -   carboxymethyl cellulose at a concentration of about 0.80% w/v;    -   sodium chloride at a concentration from about 0.025% to about        0.05% w/v;    -   benzalkonium chloride at a concentration of about 0.007% w/v;        and    -   a buffer at a concentration from about 4.0 millimolar to about        5.0 millimolar selected from the group consisting of phosphate        buffer and borate buffer.        In another embodiment, the ophthalmological composition        comprises:    -   aceclidine at a concentration of about 1.35% w/v;    -   tropicamide at a concentration of about 0.044% w/v;    -   polyoxyl 40 stearate at a concentration from about 5.0% to about        6.0% w/v;    -   carboxymethyl cellulose at a concentration of about 0.80% w/v;    -   sodium chloride at a concentration from about 0.025% to about        0.05% w/v, preferably from about 0.037% to about 0.05% w/v;    -   an antioxidant selected from the group consisting of disodium        ethylenediaminetetraacetic acid at a concentration from about        0.005% to about 0.50% w/v, citrate at a concentration from about        0.01% to about 0.3% w/w, Ca2DTPA at a concentration from about        0.001% to about 0.2% w/v and a combination thereof, preferably        ethylenediaminetetraacetic acid at a concentration from about        0.0001% to about 0.015% w/v; and    -   a buffer at a concentration from about 4.0 millimolar to about        5.0 millimolar selected from the group consisting of phosphate        buffer and borate buffer.        In another embodiment, the ophthalmological composition        comprises:    -   aceclidine at a concentration of about 1.35% to 1.45% w/v;    -   tropicamide at a concentration of about 0.044% w/v;    -   polyoxyl 40 stearate at a concentration from about 5.0% to about        6.0% w/v;    -   carboxymethyl cellulose at a concentration of about 0.80% w/v;    -   sodium chloride at a concentration from about 0.025% to about        0.05% w/v, preferably from about 0.037% to about 0.05% w/v;    -   an α-2 adrenergic receptor agonist at a concentration from about        0.025% to about 0.045% w/v selected form the group consisting of        brimonidine, fadolmidine and guanfacine; and    -   a buffer at a concentration from about 4.0 millimolar to about        5.0 millimolar selected from the group consisting of phosphate        buffer and borate buffer.        In another embodiment, the ophthalmological composition        comprises:

aceclidine at a concentration of about 1.40-1.45% w/v;

tropicamide at a concentration of about 0.044% w/v;

carboxymethyl cellulose at a concentration of about 0.85% w/v;

sodium chloride at a concentration of about 0.75% w/v;

wherein said composition further comprises

borate buffer at a concentration of about 10 millimolar;

benzalkonium chloride at a concentration of about 0.01% w/v,

polyoxyl 40 stearate at a concentration of about 5.5% w/v;

citrate at a concentration of about 0.2% w/v;

wherein the composition is at pH of about 7.0, and

wherein w/v denotes weight by volume.

In another embodiment, the ophthalmological composition comprises:

-   -   aceclidine at a concentration of about 1.40 w/v;    -   tropicamide at a concentration of about 0.044% w/v;    -   carboxymethyl cellulose at a concentration of about 0.80% to        about 0.85% w/v;    -   sodium chloride at a concentration of about 0.05% w/v;    -   wherein said composition further comprises    -   borate buffer at a concentration of about 10 millimolar;    -   benzalkonium chloride at a concentration of about 0.01% w/v,    -   polyoxyl 40 stearate at a concentration of about 5.5% w/v;    -   dicalcium diethylenetriamine pentaacetic acid (“Ca2DTPA”) at a        concentration from about 0.01% w/v;    -   wherein the composition is at pH of about 7.0, and    -   wherein w/v denotes weight by volume.        In another embodiment, the ophthalmological composition        comprises:

aceclidine at a concentration of about 0.5% w/v; and

poloxamer 188 at about 0.1% w/v;

poloxamer 407 at about 0.2% w/v;

polyoxyl stearate at about 5% w/v;

polyoxyl 35 castor oil at about 0.25% w/v;

carboxymethyl cellulose at a concentration of about 0.80% to about 0.85%w/v;

sodium chloride at a concentration of about 0.25% w/v;

perborate at a concentration of about 0.02% w/v;

citrate buffer at a concentration of about 15 to about 75 mM;

optionally, guanfacine at a concentration of about 0.03% w/v; and

wherein said composition has a pH of about 5.0 to about 8.0; andpreferably, about 5.9 to about 6.2; and

wherein w/v denotes weight by volume.

The following Examples are provided solely for illustrative purposes andare not meant to limit the invention in any way.

EXAMPLES Example 1 Effect of Aceclidine on Vision of Subjects Aged 47 to67 Years

Table 1 demonstrates the effect on the near focus ability of presbyopicsubjects before and after ophthalmological administration of acomposition containing aceclidine. Each composition included aceclidinein the concentrations indicated and 5.5% w/v HPβCD, 0.75% w/v CMC, 0.25%w/v NaCl and 0.01% w/v BAK. Additionally compositions administered tosubjects 4 and 5 included 0.125% w/v tropicamide. As aceclidine is anenantiomer, the clinical effectiveness may vary with different ratios.For the present studies a nearly exact 50:50 ratio of stereoisomers wasmeasured as best determined by polarimetry.

TABLE 1 Effects of aceclidine on vision of presbyopic patients. VisionBaseline Post Gtt 15″ Aceclidine R Pre L Pre R Pre L Pre R Post L Post RPost L Post Effect Date # Age % Dist Dist Near Near Dist Dist Near Near(h) Aug. 21, 2013 1 67 1.5 20.20 20.30 20.60 20.60 20.20 20.20 20.1520.15 9.00 Aug. 22, 2013 2 52 1.5 20.30 20.30 20.50 20.50 20.25 20.2520.25 20.20 8.00 Aug. 23, 2013 3 61 1.5 20.40 20.30 20.60 20.50 20.2020.25 20.15 20.15 8.00 Aug. 23, 2013 4 61 1.1 20.20 20.25 20.80 20.5020.15 20.15 20.20 20.15 12.00 Aug. 23, 2013 5 53 1.1 20.20 20.20 20.6020.60 20.20 20.20 20.25 20.25 7.00 Aug. 24, 2013 6 47 1.5 20.25 20.2520.100 20.100 20.20 20.20 20.15 20.15 8.00 Aug. 25, 2013 7 58 1.5 20.3020.200 20.100 20.30 20.25 20.30 20.20 20.30 8.00

As seen in Table 1 all subjects had less than perfect near vision(20.20) in both the left and right eye (object at 15 inches from theeye) and most subjects had less than perfect distance vision beforeadministration of the composition. After administration of thecomposition all subjects experienced an improvement in their near visionthat lasted from 7 to 12 hours. Surprisingly, the majority of subjectsalso experienced improvement of their distance vision for the same timeperiod. Still more surprisingly the improvement in near point was muchcloser than 16″ typically required for comfortable reading, in somecases to about 8.5″ more commonly seen in individuals 30 or less. Theaddition of tropicamide, a cycloplegic agent, had no additive ordeleterious effect on vision correction.

Example 2

TABLE 2 Effect of concentration of concentration of aceclidine andtropicamide. #5 #5 #1 #2 #3 #4 (OD) (OS) #6 #7 Brimonidine   0.03%  0.03% 0.03% 0.03% 0.03% 0.03% 0.03% Poloxamer 407  5.5% HPBCD  5.5%5.5% 5.5% 5.5% 5.5% 5.5% 5.5% Aceclidine  1.5%  1.5% 0.75% 1.1% 1.1%1.1% 1.1% 1.1% Tropicamide 0.014% 0.021% 0.028% 0.042% 0.062% NaCl  0.25%   0.25% 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% CMC   0.75%   0.75%0.75% 0.75% 0.75% 0.75% 0.75% 0.75% BAK  0.1%  0.1% 0.1% 0.1% 0.1% 0.1%0.1% 0.1% Redness (15 m) 3+  1  0.5 0.5 0 0 0 0 Redness (30 m) 1.5 0.50.25 0.25 0 0 0 0 Brow Ache (60 m) 2+  2+  2 0.5 0.5 0.0 0.0 0.0Stinging (10 m) 2  2  0.5 0 0 0 0 0 BD-OD 20.20 20.20 20.20 20.20 20.2020.20 20.20 20.20 BD-OS 20.25 20.25 20.25 20.25 20.25 20.25 20.25 20.25BN-OD 8 pt 8 pt 8 pt 8 pt 8 pt 8 pt 8 pt 8 pt BN-OS 7 pt 7 pt 7 pt 7 pt7 pt 7 pt 7 pt 7 pt BP-photopic   3 mm   3 mm   3 mm   3 mm   3 mm   3mm   3 mm   3 mm BP-mesopic   5 mm   5 mm   5 mm   5 mm   5 mm   5 mm  5 mm   5 mm Miosis start (m) 15   15   15 15 15 15 15 15 Miosis (OU)(1 hr) 1.63 mm  1.63 mm  2.0-2.5 1.63 mm  1.63 mm  1.63 mm  1.63 mm 1.70 mm  mm Distance (OU) 20.20 20.20 20.20 20.20 20.20 20.20 20.2020.20 (20 m) Distance (OD) 20.15 + 2 20.15 + 2 20.20 20.15 + 2 20.15 + 220.15 + 2 20.15 + 2 20.15 + 2 (1 hr) Distance (OS) (1 hr) 20.15 + 220.15 + 2 20.20 20.15 + 2 20.15 + 2 20.15 + 2 20.15 + 2 20.15 + 2Disance (OU) (1 hr) 20.10 − 3 20.10 − 3 20.15 20.10 − 3 20.10 − 3 20.10− 3 20.10 − 3 20.10 − 3 Near (OU) (20 m) 4 pt 4 pt 4 pt 4 pt 4 pt 4 pt 4pt 4 pt Time (hr) 12.5  12.5  6.5 11 10 10 Abbreviations: (C) indicatescorrected vision, (m) indicates minutes, (hr) indicates hour, mmindicates millimeters, BD indicates baseline distance vision; BNindicates baseline near vision, BP indicates baseline pupil size, ODindicates right eye; OS indicates left eye and OU indicates both eyes.All percentages are w/v. “pt” reflects size of print materials, 4 beingequivalent to 20/20 vision and 3 to 20/15 vision. “Time” refers toduration of the effect.

As seen in Table 2 aceclidine at a concentration of at least 1.1% w/vwas able to reduce the size of the pupil to 1.63 mm 1 hour afterinstillation resulting in corrected near and distance vision for atleast 10 hours. Lowering of the concentration of aceclidine to 0.75% w/v(formula #3) reduced the miotic effect to 2.0-2.5 mm after 1 hour andvision correction lasted only 6.5 hours. The addition of 0.03% w/vbrimonidine reduced redness of the eye (4 out of 4 without brimonidine,not shown) to 1.5 out of 4 within 30 minutes after instillation whichwas maintained for the entire time vision was corrected. Switching thenonionic surfactant to HPβCD (formulas #2-6) further reduced the rednessof the eye. Lowering of the concentration of aceclidine to 0.75% w/v(formula #3) further reduced eye redness but as mention above alsoreduced the vision correction duration of the formula.

A brow ache and stinging in the eye were noticeable in formulas #1-3with a 2 out of 4 level of pain which was also associated with feelingsof slight nausea, upset stomach and fatigue. Surprisingly, the additionof a cycloplegic agent, tropicamide, reduced brow ache and stinging to0.5 out of 4 and 0 out of 4 respectively with brow ache dissipatingafter 60 minutes (formula #4). Further, the raising of the concentrationof aceclidine to 1.1% w/v restored the longer duration of correctedvision seen in formulas #1-2 without increasing eye redness. However,upon re-instillation of formula #4 at the end of the 10 hours noticeablebrow ache occurred. Instillation of formula #5 (OD) and (OS), withincreased tropicamide concentrations, following formula #4 relieved thebrow ache experienced with re-installation of formula #4. Upon a 3^(rd)instillation, at the end of the effective duration of formula #5,re-instillation of formula #5 again led to considerable brow ache. Onceagain, in formula #6, raising the concentration of tropicamide was ableto overcome the brow ache. Additionally and unexpectedly, tropicamide,despite being a cycloplegic agent, had no effect on pupil miosis orvision correction. Surprisingly, the addition of tropicamide resulted ina prolonged duration of optimal pupil size constriction.

To determine the effect of brimonidine on pupil miosis, formula #7, wasadministered. Administration of formula #7 resulted in only a slightdecrease in pupil miosis to 1.70 mm with identical distance and nearvision improvement to that of formula #5. A 2-3+ conjunctival injectionwas noted.

All baseline vision data was based on vision corrected with distancecontact lenses. Near vision was noted by subject as outstanding from 8inches to the horizon at 1.5 hours after installation. A MarcoAutorefractor with infrared camera and superimposed pupil calibrationscale was used for all pupil size measurements. Once an image wasselected it remained on screen allowing accurate calibration.

Example 3

TABLE 3 Effect of concentration of aceclidine, brimonidine, guanfacine,fadolmidine, tropicamide and additives. AB2T AB4T AB6T AB11T AB12TPROPH13 Aceclidine 1.55 1.55 1.55 1.55 1.85 1.55 Brimonidine 0.037 0.0370.037 0.037 Fadolmidine 0.037 Guanfacine 0.037 HPBCD 5.5 5.5 5.5 5.5 5.55 Tropic amide 0.043 0.043 0.043 0.043 0.042 0.043 CMC* 0.075 0.0750.075 0.075 0.075 0.075 NaCl 0.025 0.025 0.025 0.025 0.025 0.025 BAK0.01 0.01 0.01 0.01 0.01 0.01 Glycerin 0.1 0.1 0.1 Poloxamer 188 0.10.05 Polyoxyl 40 stearate 0.05 pH 6.5 7.5 7.5 7.5 7.0 7.5 nasalcongestion 0 0 0 0 0 0 stinging initial 0.75 0 1.5 3.5 0 1.5 stinging, 3min 0.5 0 0 wash out 0 0 redness initial 0 0 1 D/C 1 1 redness 15 min 00 0 D/C 0 0 whitening 0 0 0 D/C 1.5 1.5 pain 0 0 0 D/C 0 0 vision near20.30 20.15 20.15 D/C 20.15 20.15 vision distance 20.20 20.20 20.20 D/C20.20 20.20 onset (min) 20 12 16 D/C 12 16 duration (hrs) 5.5 7.5 7.5D/C 7.5 7.5 color clear yellow yellow yellow yellow yellow OVERALL 2.53.9 3.8 0 4 3.9 *1% = 2,500 cps All percentages are w/v. Scores fornasal congestion, stinging initial, stinging, 3 min, redness initial,redness 15 min, whitening, pain and overall are out of 4. “pt” reflectssize of print materials, 4 being equivalent to 20/20 vision and 3 to20/15 vision. Baseline vision was 20.20 both eyes for distance; 20.70right eye unaided for near; 20.80 left eye for near (best @ 16″). D/Cstands for discontinued after eye washing due to intolerable stinging.

Aceclidine at a concentration of 1.55% w/v was able to reduce the sizeof the pupil to about 1.63 min 30 minutes after instillation resultingin corrected near and distance vision to 20.20 or better for at least 6hours, with noticeable affect lasting about 7.5 hours as seen in Table3. Lowering of the concentration of aceclidine to 1.25% w/v (not shown)resulted in useful near vision improvement to about 20.25-20.30, but notas effective as at the higher dose range alkaline pH resulted in quickeronset, longer duration, and greater effect. The addition of 0.037% w/vbrimonidine reduced redness of the eye (4 out of 4 without brimonidine,not shown) to baseline within 15 minutes after instillation which wasmaintained for the about the entire time vision was corrected. Addingglycerin 0.10% w/v noticeably reduced stinging. Adding instead poloxamer188 0.05% w/v and polyoxyl 40 stearate 0.05% w/v however reduced initialstinging further but was more viscous. The combination of glycerin 0.1%w/v, poloxamer 188 0.1% w/v at a pH of 6.5 was noticeably reduced inonset, duration, comfort and effectiveness. AB11T did not includeglycerin, poloxamer 188, or polyoxyl 40 stearate, which resulted insubstantial stinging and discontinuation of the experiment with eyeflush irrigation immediately after instillation. Substitution ofguanfacine 0.037% w/v in AB12T for brimonidine resulted in minimalinitial redness with prolonged redness reduction and some degree ofwhitening, and appeared to provide overall the best cosmesis thoughrequiring slightly higher aceclidine concentration for optimal effect.

All baseline vision data was based on vision corrected with distancecontact lenses. Near vision was noted by subject as outstanding from 8to 10 inches to the horizon at 30 minutes after installation for AB4Tand AB6T.

AB4T and AB6T were repeated both monocularly and binocularly.Substantial improvement in depth perception, near point acuity to 3 pt(20.15), and near point distance (8″, 20.20) was noted when both eyeswere treated vs. monocular treatment. Monocular treatment resulted inworsening of vision with both eyes open versus testing only the treatedeye.

Example 4

TABLE 4 Effect of concentration of aceclidine, brimonidine, tropicamide,and additives. #8 #9 #10 #11 #12 #13 #14 Aceclidine 1.61% 1.61% 1.61%1.61% 1.61% 1.53% 1.53% Tropicamide 0.042% 0.042% 0.042% 0.042% 0.042%0.044% 0.044% Brimonidine 0.042% 0.042% 0.042% 0.042% 0.042% CMC 0.75%0.75% 0.80% 0.87% 0.75% 0.75% 0.75% NaCl 0.25% 0.25% 0.50% 0.50% 0.25%0.50% 0.50% BAK 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% pH 7.00 7.007.00 7.00 8.00 7.00 7.00 phosphate buffer 5 mM 5 mM 5 mM 6 mM 5 mM 5 mMborate buffer 5 mM Onset (min) 15 15 15 15 15 15 15 Duration (hrs) 7 710-12 10-12 7 9 7 Pupil range (mm) 1.5-1.7 1.5-1.7 1.5-1.7 1.5-1.71.5-1.7 1.8-2.0 1.8-2.0 Dimming 0-4 1.5 1.5 1.5 1.5 1.5 0.5 0.5 Sting0-4 1 1 1 1 1 1 1 Ache 0-4 0.25 0.25 0.25 0.25 0.25 0.00 0.00 Redness0-4 0.5 0.5 0.5 0.5 1.5 1.0 0.5 Other watery watery sl thicker slresidue watery watery watery Overall 0-5 3.5 3.5 4 4 2.5 4.5 4.75 #15#16 #17 #18 #19 #20 #21 Aceclidine 1.53% 1.53% 1.53% 1.53% 1.45% 1.65%1.75% Tropicamide 0.044% 0.044% 0.044% 0.044% 0.042% 0.044% 0.035%Brimonidine 0.042% 0.042% 0.042% 0.042% 0.042% 0.042% CMC 0.80% 0.80%0.80% 0.80% 0.75% 0.75% 0.75% NaCl 0.50% 0.75% 0.75% 1.00% 0.25% 0.25%0.25% BAK 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% pH 7.00 7.00 8.007.00 7.00 7.00 8.00 phosphate buffer 5 mM 5 mM 5 mM 5 mM 5 mM 5 mM 6 mMborate buffer Onset (min) 15 15 15 15 15 15 15 Duration (hrs) 10-12 9 97 7 7 7 Pupil range (mm) 1.8-2.0 1.8-2.0 1.8-2.0 1.8-2.0 1.8-2.1 1.8-2.11.8-2.2 Dimming 0-4 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Sting 0-4 1 1 1 1 1 1 1Ache 0-4 0.00 0.00 0.00 0.00 0.00 0.25 0.00 Redness 0-4 0.5 0.5 1.0 0.50.5 0.5 0.5 Other sl thicker sl thicker sl thicker thicker watery waterywatery Overall 0-5 5 5 5 4 4 4 4

As seen in Table 4, formulas #8-9, an increase in brimonidine to 0.42%w/v resulted in redness reduction to 0.5, while 0.75% w/v CMC resultedin a watery consistency. Unexpectedly, increasing CMC from 0.75% w/v toa range of 0.80% w/v to 0.87% w/v and increasing NaCl from 0.25% w/v to0.75% w/v in formulas #10-11 resulted in a thicker consistency and anincreased residence time from 7 hours to 10-12 hours and decreased theamount of drug that drained into the nasolacrimal duct. This decreaseddrug delivery to the nasal passages results in less nasal congestion.

In formulas #13-18 a decrease in the amount of aceclidine from 1.61% to1.53% w/v resulted in a pupil size range from 1.8-2.0 mm. Dimming as aresult of the restriction of the pupil decreased linearly from 1.5 to0.5 with the decreased amount of aceclidine. Specifically, the 1.8 to2.0 mm pupil created 41% more light than the 1.5 to 1.7 mm pupil.Surprisingly, the 1.8 to 2.0 mm pupil had a near depth increase of 1.75D. This is only a 0.25 D loss from the beneficial 2.00 D seen with the1.5-1.7 mm range. Thus, the 1.80 to 2.0 mm range produces 41% more lightwhile still allowing the full benefit of increased near vision inindividuals under 60 years of age; whereas, individuals 60 years of ageand over still experience total computer benefit and some increased nearbenefit.

The increase in tropicamide concentration from 0.042% w/v (formulas#8-#11) to 0.044% w/v (formulas #13-#18) resulted in a decrease in acheto negligible amounts. The amount of ache may also be correlated withthe age of the individual. For those individuals under the age of 45, anincrease of tropicamide concentration to a range from 0.046% to 0.060%w/v may be preferred.

Further, Table 4 shows an unexpected result seen in formulas #13 and #17where the increase of NaCl from 0.25% w/v to a range of 0.50 to 0.75%w/v resulted in an acceptable redness score of only 1.0 even without theaddition of the redness reducing agent brimonidine.

Formulas #15, #16 and #17 each result in an overall maximum rating of 5by combining the benefits of: (1) reduced aceclidine concentrations toimprove the amount of light produced without significantly affecting thenear vision benefits seen in formulas #8-#12; (2) increased NaClconcentrations resulting in a further reduction in redness even in theabsence of brimonidine; and (3) increased CMC concentrations resultingin longer residency time on the eye.

Formula #19 is an excellent alternative for the minority of individualsthat are high responders to formulas #15-#17 and get noticeable dimmingwith 1.53% w/v aceclidine. Formula #20 is an excellent alternative forthe minority of individuals that are low responders to formula #19.Lastly, Formula #21 is an excellent alternative for the minority ofindividuals that are low responders and get poor pupil response withFormula #20.

Example 5

TABLE 5 Comparison of Effects of Polyoxyl 40 Stearate, HPβCD andPoloxamer 407. #22 #23 #24 Aceclidine 1.45% 1.45% 1.45% Tropic amide0.044% 0.044% 0.044% Brimonidine 0.040% 0.040% 0.040% Polyoxyl 40Stearate 5.5% HPβCD 5.5% Poloxamer 407 5.5% CMC 0.80% 0.80% 0.80% NaCl0.037% 0.037% 0.037% EDTA 0.015% 0.015% 0.015% BAK 0.007% 0.007% 0.007%pH 7.00 7.00 7.00 phosphate buffer   5 mM   5 mM   5 mM Nasal Congestion0.00 0.50 1.50 Stinging 0.25 0.25 0.25 Wetting 4.00 4.00 4.00 Redness0.25 0.50 0.50 Visual Blur (<15 sec) 0.50 0.50 1.50 Duration 6-8 hrs 6-8hrs 6-8 hrs Overall 0-4 4.00 4.00 4.00

Clinical Protocol

20 presbyopic patients with full distance correction were each given oneof the above formulas (#22-#23). All patients received pre- andpost-drop distance and near acuity measurement, Zeiss Visante® (Visanteis a registered trademark of Carl Zeiss Meditec AG) optical adherencetomography, axial length and contrast acuity testing (i.e.Colenbrander-Michelson 10% Lum target) with the following results:

-   -   1) all patient achieved a miotic pupil of 1.5 to 2.20 mm;    -   2) no patient experienced ciliary ache, ciliary spasm, or        induced accommodation;    -   3) all patients achieved 20/30+ visual acuity or better at 14″        and were very satisfied with their high contrast near vision        results and there was no significant complaint of burning or        aching;    -   4) the duration of effect lasted 6-8 hrs in all cases;    -   5) binocular vision afforded all patients 1-1.5 additional lines        of near acuity over monocular testing;    -   6) the last 10 patients were tested at 20″ (i.e. computer        distance, cell phone distance) and all achieved 20/25 or better        near visual acuity;    -   7) moderately hyperopic (approx. +2.25 sphere) uncorrected        presbyopes were very satisfied with distance visual acuity that        improved to a 20/25 or better level at distance and near vision        in the 20/30 range; and    -   8) uncorrected distance acuity was often improved for those        patients who chose not to routinely correct a small refractive        error.

As seen in Table 5, the use of polyoxyl 40 stearate provides the mostcomfortable aceclidine formulation with the least amount of visual blurand redness. To achieve similar results to that of formula #22, formula#23 requires 10-15% higher concentrations of the non-ionic surfactantand formula #24 requires 15-20% higher concentrations of the non-ionicsurfactant. HPBCD induced a color change over time, possibly indicativeof oxidation. Captisol® (sulfobutylether β-cyclodextrin) was substitutedwith similar findings.

Example 6 Modulation of Aceclidine Concentrations in a PreferredEmbodiment

Preferred Embodiment:

Aceclidine 1.35%-1.55% w/v;

Polyoxyl 40 stearate 5.5% w/v;

NaCl 0.037% w/v;

CMC 0.80% w/v;

EDTA 0.015% w/v;

BAK 0.007% w/v;

Phosphate or Borate buffer 5 mM; and

pH 7.0.

For 1.35% w/v aceclidine—

-   -   1) Stinging on instillation 0.25/4.0 (lasting about 2-5        seconds);    -   2) Induced redness at 10 minutes: 1.0 to 1.5/4.0;    -   3) Induced redness at 30 minutes: 0.0 to 0.25/4.0;    -   4) Comfort: very high.    -   5) Wetting: very high, the eye maintaining sensation of improved        wetting for most of a 24 hour period after a single        instillation.    -   6) Depth of Focus distance: excellent.    -   7) Depth of Focus near: excellent.

In testing the above formulations on several subjects it was discoveredthat there is a slight range in clinical effect depending on theconcentration of aceclidine, where 1.35%-1.55% w/v aceclidine ispreferred, but for which 1.35% w/v and 1.45% w/v confer the desiredbenefits on most subjects.

Further, it is discovered that the clinical effect of 1.35% w/vaceclidine can be improved when instilled as follows:

1) baseline effect: 1 drop to each eye.

2) enhanced effect: 2 drops to each eye.

3) greater effect: after 2) above repeat 1) above.

4) maximum effect: after 2) above repeat 2) above.

Example 7 Use of a Preferred Embodiment to Prolong Contact Lens Wear

Preferred Embodiment:

Aceclidine 1.45% w/v;

Polyoxyl 40 stearate 5.5% w/v;

NaCl 0.037% w/v;

CMC 0.80% w/v;

EDTA 0.015% w/v;

BAK 0.007% w/v;

Phosphate or Borate buffer 5 mM;

pH 7.0

As a baseline, the subject, who normally wore extended wear lenses (AirOptix®; Air Optix is a registered trademark of Novartis AG) for dailywear only, slept in these lenses overnight. On arising each morning thesubject's vision was blurred and the contact lenses required removal andcleaning of film and deposits that had formed overnight. Average visionon arising at distance: 20.60; average vision at near on a Michelsoncontrast acuity chart: 20.80.

Then, for seven consecutive days the above formulation was instilledbetween 7 am and 10 am each day as a single dose. Subject wore the AirOptix® lenses throughout each day and slept in the lenses overnight.Upon arising each morning the subject's vision at distance: 20.20+;vision at near 20.40 unaided (consistent with subject's baselinepresbyopia when the subject did not wear the lenses overnight andinstead inserted the lenses upon arising).

Example 8

Table 6. Comparison of Effects of Polyoxyl 40 Stearate and Captisol®(sulfobutylether β-cyclodextrin).

TABLE 6 Comparison of Effects of Polyoxyl 40 Stearate and Captisol ®(sulfobutylether β-cyclodextrin). #25 #26 #27 #28 #29 #30 #31 #32 #33Aceclidine 1.35% 1.35% 1.35% 1.35% 1.35% 1.35% 1.35% 1.35% 1.35%Tropicamide 0.044% 0.044% 0.044% 0.044% 0.044% 0.044% 0.044% 0.044%0.044% Polyoxyl 40 stearate 5.5% 5.5% 5.5% 5.5% 5.5% 5.5% 5.5%Captisol ® 5.5% 5.5% Cocamidopropyl betaine 0.10% EDTA 0.015% 0.015%0.005% 0.005% 0.005% 0.005% 0.015% CMC 1% = 2,500 cps 0.80% 0.80% 0.80%0.80% 0.80% 0.80% 0.80% 0.80% 0.80% NaCl 0.037% 0.037% 0.037% 0.037%0.037% 0.037% 0.037% 0.037% 0.037% Mannitol 4% 4% BAK 0.007% 0.007%0.007% 0.007% 0.007% 0.007% 0.007% 0.007% 0.007% Borate buffer (mM) 4 44 4 4 4 4 Phosphate buffer (mM) 4 4 pH 7 7 7 7 7 7 7 7 7 Redness, 10 min1.25 1.25 2 2 1.75 1.75 0 0 0 Redness, 30 min 0 0 1.5 1.5 1.25 1.25 0 00 Pupil, 30 min (mm) <2 <2 <2 <2 <2 <2 <2 <2 <3 Blur on instill (sec) 1010 10 10 10 10 10 10 10 Ache 0 0 0 0 0 0 1 0 0 Rating 4.00 4.00 2.002.00 2.50 2.50 1.00 5.00 TBD

As seen in Table 6, when using polyoxyl 40 stearate as the surfactantthe exclusion of EDTA results in reduced redness and best overall ratingamong polyoxyl 40 stearate compositions (Formulas #25 and #26). Theaddition of cocamidopropyl betaine (“CAPB”) further reduces rednesshowever results in significant ache (Formula #31). Replacing polyoxyl 40stearate with Captisol® (sulfobutylether β-cyclodextrin) and addingmannitol achieves similar results in redness reduction as the additionof CAPB to polyoxyl 40 stearate but without the attendant ache resultingin the highest overall rating among aceclidine compositions (Formula#32). After several weeks formulations with Captisol® (sulfobutyletherβ-cyclodextrin) had an orange hue, possibly indicative of oxidation.

Example 9 Use of a Preferred Embodiment

Composition Tested:

-   -   aceclidine at a concentration of about 0.5% w/v; and    -   poloxamer 188 at about 0.1% w/v;    -   poloxamer 407 at about 0.2% w/v;    -   polyoxyl stearate at about 5% w/v;    -   polyoxyl 35 castor oil at about 0.25% w/v;    -   carboxymethyl cellulose at a concentration of about 0.80% to        about 0.85% w/v;    -   sodium chloride at a concentration of about 0.25% w/v;    -   optionally, BAK at a concentration of about 0.01% w/v;    -   citrate buffer at a concentration of about 0.02%;    -   with and without guanfacine at a concentration of about 0.03%        w/v; and    -   wherein said composition has a pH of about 5.0 to about 8.0; and        preferably, about 5.9 to about 6.2; and    -   wherein w/v denotes weight by volume

The composition as described above was administered to a 61 year oldsubject and was reinstalled after 1 hour. It resulted in pupils of 1.6mm ou, 20.20+ reading vision, and 20.20+ distance vision No ciliaryspasm or loss of distance vision resulted. Transient redness of about2+/out of 4 was noted for about 20 minutes without guanfacine, whereastransient redness of about 0.5+/out of 4 lasting less than 5 minutes wasnoted with guanfacine; otherwise the clinical results were identical.The presence or absence of BAK had no clinical effect, and was used toprovide an optional preservative.

What is claimed is:
 1. An ophthalmological composition for the treatmentof presbyopia comprising aceclidine at a concentration from about 0.25%to about 2.0% w/v and a cycloplegic agent at a concentration from about0.025% to about 0.1% w/v, wherein w/v denotes weight by volume.
 2. Theophthalmological composition according to claim 1, wherein thecycloplegic agent is tropicamide.
 3. The ophthalmological compositionaccording to claim 1, further comprising brimonidine.
 4. Theophthalmological composition according to claim 1 further comprising asurfactant selected from the group consisting of an anionic surfactant,a nonionic surfactant, and a combination thereof.
 5. Theophthalmological composition according to claim 4 further comprising aviscosity enhancer.
 6. The ophthalmological composition according toclaim 5 wherein: the viscosity enhancer is carboxymethyl cellulose orhydroxypropylmethyl cellulose; the anionic surfactant is selected fromthe group consisting of a gamma cyclodextrin, sulfobutyletherβ-cyclodextrin, 2-hydroxypropyl cyclodextrin, sodium lauryl sulfate andsodium ester lauryl sulfate; and the nonionic surfactant is selectedfrom the group consisting of polyoxyl stearate, a poloxamer, apolysorbate, sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan monooleate, a polyoxyl alkyl, a polyoxylstearate, a cyclodextrin and derivatives thereof.
 7. Theophthalmological composition according to claim 2 wherein aceclidine isat a concentration from about 1.35% to about 1.55% w/v and tropicamideis at a concentration of about 0.042% w/v.
 8. A method of treatingpresbyopia comprising administering to a subject in need thereofaceclidine at a concentration from about 0.25% to about 2.0% w/v andfurther comprising administering concurrently or sequentially anophthalmological composition comprising a cycloplegic agent at aconcentration from about 0.025% to about 0.1% w/v, wherein w/v denotesweight by volume.
 9. The method of claim 8 wherein the cycloplegic agentis tropicamide at a concentration of 0.042% w/v and wherein theophthalmological composition further comprises: hydroxypropylmethylcellulose; sodium chloride at a concentration from about 0.05% to about1.1% w/v; glycerin at a concentration of about 0.2% w/v; and citrate ata concentration of about 0.2% w/v or a phosphate buffer at aconcentration from about 5 to about 10 millimoles, and wherein w/vdenotes weight by volume.
 10. The method of claim 8 wherein thecycloplegic agent is tropicamide at a concentration of 0.042% w/v andwherein the ophthalmological composition further comprises:hydroxypropylmethyl cellulose; sodium chloride at a concentration fromabout 0.05% to about 1.1% w/v; polyoxyl 40 stearate at a concentrationof about 5.5% w/v; and citrate at a concentration of about 0.2% w/v or aphosphate buffer at a concentration from about 5 to about 10 millimoles,and wherein w/v denotes weight by volume.
 11. The method of claim 8wherein the aceclidine and the ophthalmological composition areadministered from one device with at least two chambers and wherein theaceclidine resides in a first chamber and the ophthalmologicalcomposition resides in a second chamber and wherein the aceclidine firstcontacts the ophthalmological composition at the time of administration.12. The method of claim 8 wherein the aceclidine resides in a first vialand the ophthalmological composition resides in a second vial and theaceclidine first contacts the ophthalmological composition at the timeof administration.
 13. The ophthalmological composition according toclaim 7 further comprising a surfactant at a concentration of about 5.5%w/v.
 14. The ophthalmological composition according to claim 13 whereinthe surfactant is polyoxyl 40 stearate.
 15. An ophthalmologicalcomposition for the treatment of presbyopia comprising aceclidine at aconcentration from about 1.40 to about 1.45% w/v, tropicamide at aconcentration of about 0.042% w/v, polyoxyl 40 stearate at aconcentration of about 5.5% w/v, and hydroxypropylmethyl cellulose,wherein w/v denotes weight by volume.